Table of contents :

• intracellular [H⁺] = 1^.10^-3-4^.10^-5 mEq/L => pH = 6-7.4

• organelles : any of the membrane-bound organized cytoplasmic structures of distinctive morphology and function(metabolically active) present in all eukaryotic cells
• plasma or cytoplasmic membrane (or plasmalemma) and membrane traffic
• E-side (for ectoplasmic)
• P-side (for protoplasmic)
• unit membrane : the trilaminar structure of the plasma membrane as seen under the electron microscope and postulated to be the same for the membranes of all cells, the cell nucleus, and organelles (mitochondria, etc.).
• glycocalyx / glycocalix : the glycoprotein and polysaccharide covering that surrounds many cells; in bacterial cells the glycocalyx forms masses of fibers that extend from the cell and by means of which the cell adheres to surfaces.
• membrane microdomains have a different composition from that of the surrounding membrane
• coated pits
• caveolae-related lipid rafts (CLRs) / nonionic detergent-insoluble glycolipids (DIG) / detergent-resistant membranes (DRM) / cholesterol- and glycosphingolipid-enriched microdomains : cell membraes are composed mainly of (glycero)phospholipids, (glyco)sphingolipids and cholesterol. Phospholipids usually contain unsaturated acyl chains and, therefore, tend to be loosely packaged in bilayers, forming liquid-disordered membranes that allow rapid lateral and rotational movement of lipids. By contrast, sphingolipids contain long, saturated acyl-chains that pack tightly, forming quasi-gel membranes with reduced movement. It is thought that spingolipids are enriched in the external leaflet of the bilayer, and are connected to phospholipids that contain saturated fatty acids in the inner leaflet. Cholesterol partitions preferentially in bilayers that contain saturated fatty acids, promoting the transition from the quasi-gel phase to a more fluid liquid-ordered conformation, which allows substantial lateral mobility. These membranes in liquid-ordered conformation are known as "rafts", as they float in the liquid-disordered phospholipid phase. Rafts can selectively recruit or exclude membrane proteins. Constitutively associated raft proteins are glycosylphosphatidylinositol (GPI) anchored (linked to the exoplasmic plasma membrane leaflet), doubly acylated (anchored to the cytoplasmic leaflet or cholesterol binding). By contrast, membrane-spanning and prenylated proteins partition poorly in rafts. Palmitoylation and oligomerization increase the partitioning of some transmembrane proteins to rafts^ref. So, there is a broad spectrum of cell mechanisms that regulate the proteins into and outside of rafts. Cholesterol is the dynamic glue that holds rafts lipids together, and its removal from the membrane results in dispersion of raft-associated lipids and proteins. Rafts nonetheless form and function in the absence of glycosphingolipids. Several methods have been used to study rafts in cell membranes :
• isolation of detergent-resistant membranes (DRMs) using non-ionic detergents in flotation density gradients is a biochemical approach that is frequently used to identify raft-associated proteins in cells : relative insolubility of membrane-raft lipids. However, DRMs are post-lysis membrane aggregations, which might exclude proteins that are weakly associated with rafts or include proteins that are not initially part of these microdomains
• antibody-induced lateral co-patching : co-localization in patches of proteins that share compatible lipid environments
• fluorescence resonance energy transfer (FRET) analysis (cholesterol-sensitive changes in proximity measurements between raft markers) indicated that there was a concentration of raft-associated markers in microdomains in some instances, whereas in other studies, FRET was independent of receptor clustering in microdomains
• atomic force microscopy (AFM) : tracking of single lipid or protein molecules, associted with or dissociated from rafts
They can be disrupted using methyl-b-cyclodextrin (MbCD). They act in organizing the cell's numerous signal-transduction pathways into a coherent whole. It's ineffiecient for randomly distributed proteins to somehow piece together an ad hoc pathway in response to each incoming signal; instead, pathways are likely to be preassembled. This would also facilitate the "cross-talk" that often occurs between different pathways, as the components for such interaction could be located in the same caveolae.
• phospholipid scramblase 1 (PLSCR1)
• raft-linking protein (RAFTLIN)
• Wiskott-Aldrich syndrome protein (WASp)
• stomatin (STOM) : a major lipid-raft component of erythrocytes, a granules of platelets, specific and azurophil granules of neutrophils, and epithelial cells
• CD9
• CD36
• integrin a_IIbb₃
• GLUT-3
• flotillin 1 (FLOT1)
• flotillin 2 (FLOT2)
Examples of pathogens that hijack rafts :
• bacteria :
• Campylobacter jejuni (intracellular survival)^ref
• Legionella pneumophila (intracellular survival)^ref
• Pseudomonas aeruginosa (host response, signalling)^ref
• Brucella spp. (entry/intracellular survival)^{ref1, ref2}
• FimH and Dr⁺ Escherichia coli (entry/intracellular survival)^{ref1, ref2}
• Salmonella typhimurium (entry/intracellular survival)^{ref1, ref2}
• Shigella flexneri (entry/intracellular survival)^ref
• Chlamydiophila spp. (entry/intracellular survival)^ref
• Mycobacterium spp. (entry/intracellular survival)^{ref1, ref2}
• Vibrio cholerae (cytolysin binding/oligomerization)^ref
• Aeromonas hydrophila (aerolysin binding/oligomerization)^ref
• Clostridium spp. (toxin binding/oligomerization)^{ref1, ref2, ref3, ref4, ref5, ref6}
• Streptococcus pyogenes (streptolysin O oligomerization)^ref
• Bacillus anthracis (anthrax toxin oligomerization)^ref
• Bacillus thuringiensis (Cry1A toxin binding/oligomerization)^ref
• Helicobacter pylori (vacuolating cytotoxin oligomerization/signalling)^ref
• Listeria monocytogenes (listeriolysin O oligomerization/signalling)^ref
• viruses
• simian virus 40 (entry/trafficking)^{ref1, ref2}
• echovirus 11 (entry/trafficking)^ref
• echovirus 1 (entry)^ref
• avian sarcoma and leukosis virus (entry)^ref
• Semliki forest virus (entry/budding)^{ref1, ref2}
• ecotropic mouse leukemia virus^ref
• HTLV-1 (entry/budding)^{ref1, ref2}
• HIV-1 (entry/budding/transcytosis)^{ref1, ref2, ref3}
• Ebola virus and Marburg virus (entry/budding)^ref
• measles virus (budding)^ref
• HHV-1 / HSV-1 (budding)^ref
• Influenzaviruses (budding)^ref
•  HHV-4 / EBV(signalling)^ref
• protozoa
• Toxoplasma gondii (intracellular survival)^ref
• Plasmodium falciparum (entry/intracellular survival)^ref
• Theileria parva (signalling)^ref
It has been indicated that cell membranes might have various raft subtypes, on the basis of different detergent solubility or ganglioside composition. Cells might use protein segregation in distinct rafts subtypes to target specific proteins to spatially restricted membrane locations in polarized neurons, epithelial cells or migrating lymphocytes.
‡ + polymerization of caveolins
• caveolin-1 (CAV1) (22 kDa, a and b isoforms from alternative initiation codon in the same reading frame; it links integrin subunits to the tyrosine kinase FYN, an initiating step in coupling integrins to the Ras-ERK pathway and promoting cell cycle progression. So it acts as a tumor suppressor by binding kinases in their catalytically active sites, thereby blocking their activity; it is often deleted or down-regulated in cancer cells (16% of human breast cancers)
• CAV1 and caveolin-2 (CAV2) (20 kDa; a and b isoforms from alternative initiation codon in the same reading frame) are located next to each other on chromosome 7 and express colocalizing proteins that form a stable hetero-oligomeric complex)
• other proteins, ...
=> invagination :
• caveolae : these flask-shaped "small caves" found in most cell types act in signal transduction and transporting materials (including cholesterol) into and through cells and present caveolins in inner surface. Apart from caveolins, caveolae also contain serum deprivation response (SDR / SDPR) / phosphatidylserine binding protein, but not clathrin. Caveolin-interacting proteins are Neu3 sialidase and dysferlin (whose mutations cause LGMD2B). Mutations in caveolin-3 (CAV3) / M caveolin (expressed in skeletal, cardiac, and smooth muscles. Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain 2 potential translation initiation sites) cause limb-girdle muscle dystrophy type 1C (LGMD1C). Because of the crosstalk between lipid rafts and caveolaee, it is not surprising that caveolae are enriched in raft-associated proteins and that all of the caveolins also partition into rafts. Caveolin-deficient mice lack caveolae, although most of the functions of lipid rafts are normal in these animals.
Web resources :
• Structure of fluid lipid bilayers
• Presynaptic proteins, synatptic vesicle docking and membrane fusion
• Signal sequence at COPE
• cell body : that portion of a cell which contains the nucleus, independent of any such projections as an axon or dendrites which the cell may have
• nucleus / karyon : a cell nucleus: a spheroid body within a cell, consisting of a number of characteristic organelles visible with the light microscope, a thin nuclear membrane, a nucleolus or nucleoli, irregular granules of chromatin and linin, and a diffuse nucleoplas. As more processing of the primary transcript (hnRNA) is needed before it can be translated this type of separation is necessary.
• karyocyte : a nucleated cell
• nuclear envelope or membrane / karyolemma / karyotheca
• perinuclear cisterna or space : the space separating the inner from the outer nuclear membran
• nuclear pore complexes (NPC) : the NPC is a large complex of about 125 MDa and is composed of 50-100 different proteins, termed nucleoporins, arranged in a 8x pattern to create a structure whose inner hole is 9 < Ø < 26 nm. Molecules with Ø < 9 nm (protein smaller than 60 kDa and ODN or small DNA fragments up to 200 bp) can diffuse passively through the central channel of the NPC. Larger molecules comprising of protein complexes are transported actively by nuclear transport receptors through the NPC, thereby the NPC is capable of dilating up to 10-25 nm. Physiological factors can induce structural changes of the NPC modifying its permeability. Indeed, cytoplasmic ATP concentrations can modulate size and shape of the NPC. Furthermore, calcium depletion from the nuclear envelope cisterna inhibits passive diffusion and NLS-mediated transport through the NPC, probably by inducing conformational changes. The broad variety of import substrates led the cell to develop a wide range of specific nuclear import pathways with corresponding regulation mechanisms, from which the importin b-pathway is one of the best characterized.
• importin b₁
• importin b₂
• importin b₃
Import substrates bind either directly to a importin b or through the adapter protein importin a.
• importin a₁ / karyopherin a₂
• importin a₃ / karyopherin a₄
• importin a₄ / karyopherin a₃
• importin a₅ / karyopherin a₁
• importin a₆ / karyopherin a₅
• importin a₇ / karyopherin a₆
The latter situtation is found for cargoes bearing a "classical", Arg/Lys-rich NLS, such as for the SV40 large T antigen or nucleoplasmin (2 and 3). Leptomycin B (LMB) is a specific inhibitor of nuclear export that interferes with the interaction between NESs and CRM1 / exportin 1, a NES receptor belonging to the b-importin family required for chromosome region maintenance. The cargo/importin complex docks through the association of other factors to cytoplasmic filaments emanating from nucleoporins and translocates through the central channel by a still unknown mechanism. The central channel constitutes a hydrophobic meshwork composed of the Phe-rich repeats from specific nucleoporins. Finally, the complex dissociates by an energy-consuming reaction and transport factors are recycled back to the cytosol and are thus available for a next import cycle. One important factor is the small GTPase Ran, which allows association of the cargo-importin complex in its GDP-form, whereas its GTP-form dissociates the complex. The GDP- and GTP-form are maintained respctively by the Ran GTPase activating protein 1 (RanGAP1) in the cytoplasm and the nucleotide exchange factor RanGEF in the nucleoplasm. Therefore, directionality of the transport is dictated by the unequal distribution of RanGAP1 and RanGEF between the cytoplasm and the nucleus.
Web resources : Nucleocytoplasmic transport: signals, mechanisms and regulation
The nuclear envelope's incipient function was to allow mRNA splicing, which is slow, to go to completion so that translation, which is fast, would occur only on mRNA with intact reading frames. The rapid, fortuitous spread of introns following the origin of mitochondria is adduced as the selective pressure that forged nucleus–cytosol compartmentalization^ref
• nuclear content / karyoplasm / nucleoplasm : protoplasm of the nucleus of a cell.
• nucleochylema : the ground substance of the nucleus of a cell as distinguished from that of the cytoplasm.
• parachromatin : a chromatophil substance contained in the finer part of the nuclear substance, as in the nucleoplasm of the spindle in karyokinesis.
• karyolymph / karyenchyma / karyochylema / nucleochyme / nuclear juice : the liquid part of a cell nucleus
• achromatin : the faintly staining substance forming the karyolymph, linin, and nuclear membrane of the nucleus of a cell.
• nuclear matrix / karyoskeleton / karyoreticulum : the fibrillar part of the karyoplasm as distinguished from the fluid part of karyolymph
• linin / nucleohyaloplasm : the faintly staining substance composing the fine, netlike threads found in the nucleus of a cell, where it bears the chromatin in the form of granules
• chromidial apparatus : the chromatin staining material of the cytoplasm of a cell, occurring in the form of granules, rods, strands, and networks
• chromatin / karyotin (nDNA + histones + protamines)
• euchromatin : the condensed state of chromatin in which it stains lightly, is genetically active, and is partially or fully uncoiled, being the interphase form of the chromosome or the material of most chromosome arms during metaphase
• heterochromatin : that state of chromatin in which it is dark-staining and tightly coiled, forming irregular clumps (karyosomes) or Barr bodies in the nuclei of cells in interphase, or stains densely in certain areas of mitotic chromosomes.
• constitutive heterochromatin : the chromatin in regions of the chromosomes that are invariably heterochromatic, located in secondary constrictions of chromosomes 1, 9, and 16, the distal end of the long arm of the Y chromosome, and the centromeric and telomeric regions; it contains highly repetitive sequences of DNA that are genetically inactive, and serves as a structural element of the chromosome
• facultative heterochromatin : the chromatin in regions of the chromosomes that become heterochromatic in certain cells and tissues; e.g., it makes up the inactive X chromosome in female somatic cells.
• nuclein : a decomposition product of nucleoprotein intermediate between native nucleoprotein and nucleic acid. It is a colorless, amorphous compound, soluble in dilute alkalis, but insoluble in dilute acids. The nucleins consist of nucleic acid and bases which vary in the different nucleins
• nucleoglucoprotein : a combination of a nucleoprotein with a carbohydrate
• nucleohistone : a complex nucleoprotein made up of deoxyribonucleic acid (DNA) and a histone, the principal constituent of chromatin
• nucleoplasmin : any of a family of acidic nuclear proteins that act as molecular chaperones, mediating the assembly of nucleosomes; nucleoplasmin transiently reduces the positive charges on histone proteins to prevent incorrect nonspecific aggregation of histones and DNA.
• nucleoprotein : a substance composed of a simple basic protein, usually a histone or protamine, combined with a nucleic acid.
• deoxyribose nucleoprotein : a deoxyribonucleic acid–protein complex.
• ribose nucleoprotein : a ribonucleic acid–protein complex.
• nucleoreticulum : any intranuclear network.
• chromatic membrane : a continuous layer of chromatin substance situated on the internal surface of a nuclear membrane
• karyomicrosome / nucleomicrosome : any of the minute segments of a chromatin fiber
• sex chromatin / Barr body /drumstick : a chromatin mass in the nucleus of female interphase cells of most mammalian species, including humans (expecially in neutrophilic PMN granulocytes). It represents a single, inactive, condensed X chromosome. See Lyon hypothesis, under hypothesis.
• nucleolus / micronucleus : a rounded refractile body present in the nucleus of most cells, which is the site of synthesis of ribosomal RNA, becoming enlarged during periods of synthesis and atrophied during quiescent periods. Multiple nucleoli occur in some cells. Proteins that are stably associated, such as RNA polymerase I subunits and small nuclear ribonucleoprotein particle complexes, exit from or accumulate in the nucleolus with similar kinetics, whereas protein components of the large and small ribosomal subunits leave the nucleolus with markedly different kinetics^ref.
• pars granulosa / nucleolonema / nucleoloneme  : a network of strands formed by organization of a finely granular substance, perhaps containing ribonucleic acid, in the nucleolus of a cell.
• nucleolar- or nucleolus-associated chromatin : heterochromatin containing DNA, situated around, and sometimes extending into, the nucleolus of a cell.
• fibrillar centers, i.e. nucleolar or nucleolus organizer regions (NORs) : material responsible for organization of the nucleolus of a cell; it is thought to comprise slender strands of heterochromatin by which satellites are attached to the rest of the chromosome.
• pars fibrosa or dense fibrillar component (DFC)
• nucleolinus : a deeply staining granule in the nucleolus.
• nucleololus / nucleolonucleus : a minute spot within the nucleolus
• secondary nucleolus : a mass sometimes seen near a nucleolus, and looking like a separated portion of the latter.
• karyosome / false nucleolus / chromatin nucleolus / chromatin reservoir / chromocenter : any of the condensed irregular clumps of chromatin dispersed in the chromatin network of a cell
• paranucleolus : a small basophil body in the enclosing sac of the cell nucleus
Web resources :
• Nuclear architecture and chromosome organization
• Dinoflagellate genome is "naked" (evolutionary link between Monera and Eukarya)
• paranucleus : a body resembling the nucleus, sometimes seen in the cell cytoplasm near the nucleus.
• paraplastin : a substance resembling parachromatin in the cytoplasm and nucleus of a cell
• mitochondria : the evolutionary transition from prokaryotes to eukaryotes—characterized by eukaryotic cells obtaining a nucleus and 2 membrane compartments—is still subject to considerable debate. It has been suggested that a nucleus developed first, followed by the acquisition of mitochondria from endocytosis of a Gram -ve Bacteria (endosymbiotic theory), a theory that has partly relied on the single-celled eukaryote Giardia intestinalis because it has a nucleus and no mitochondria, suggestive of an intermediate step, but the recent identification of highly reduced mitochondrial remnants with double membranes called mitosomes and genes (IscU and IscS) known to be involved in the biosynthesis of Fe-S clusters (a critical function of the mitochondria) in Giardia intestinalis and Trachipleistophora hominis^ref has challenged this theory. Traditional endosymbiotic models generally do not address the origin of the heterotrophic lifestyle and anaerobic energy metabolism in eukaryotes. Rather they take it as a given, a direct inheritance from the host that acquired mitochondria. Traditional models are contrasted to an alternative endosymbiotic model (the hydrogen hypothesis), which addresses the origin of heterotrophy and the origin of compartmentalized energy metabolism in eukaryotes.
• outer mitochondrial membrane : it is homologous to the outer membrane of Gram -ve Bacteria. The transport of precursor proteins across the outer membrane of mitochondria is mediated by the translocase of the outer membrane (TOM), a multicomponent proteic complex of high molecular weight that spans the membrane, forming a channel-like corridor. TOM also sorts preproteins destined for the inside of the mitochondrion from those to be inserted in the outer and inner membranes and assists in assembling these membrane proteins. The sorting and assembly machinery (SAM) is needed for the correct assembly of integral outer membrane proteins with more complicated topology, such as b-barrel proteins, after translocation of the relevant precursors through TOM : Mas37 is a protein present in the outer mitochondrial membrane and part of the SAM complex.
• inner mitochondrial membrane : it is homologous to the inner membrane of Gram -ve Bacteria
• cristae
Mitochondrial outer and inner membrane fusion events are separable and mechanistically distinct, but both require GTP hydrolysis. Homotypic trans interactions of the ancient outer transmembrane GTPase, Fzo1, are required to promote the fusion of mitochondrial outer membranes, whereas electrical potential is also required for fusion of inner membranes^ref.
• mitochondrial matrix
• mitoskeleton
• intercristal granules
• mtDNA is packaged with proteins into a nucleoid. One of the mtDNA packaging proteins is the Krebs cycle enzyme, aconitase, that the mitochondrion uses to generate metabolic energy^ref. In this second role, aconitase is required for mtDNA maintenance under particular metabolic conditions. This finding provides a direct link between energy generation and mtDNA stability, mitochondrial disease, and aging.

Web resources : Mitochondrial telomeric structures : evolution and roles in the maintenance of linear DNA genophores
Web resources : Mitochondria Research Society
• hydrogenosomes : a microbody-like membrane-bounded cytoplasmic organelle found in some protists and fungi that contains enzymes responsible for production of hydrogen gas from pyruvate. Possibly of endosymbiont origin
• chloroplasts / chloroplastids : one of the chlorophyll-bearing bodies of plant cells= arose from Cyanobacteria
• granum : a stack of ...
• thylakoid disks are disk-shaped membrane structures in chloroplasts that contain chlorophyll and where photosynthesis takes place
• endoplasmic reticulum (ER) / superior protoplasm : an ultramicroscopic organelle of nearly all cells of higher plants and animals, consisting of a more or less continuous system of membrane-bound cavities that ramify throughout the cytoplasm of a cell. 2 forms have been distinguished:
• ER cisternae
• granular or rough endoplasmic reticulum (RER) / chromidial substance / ergastoplasm bears large numbers of ribosomes on the outer surface of its membrane and is basophilic
• polyribosomes / polysomes
The ER contains chaperones that belonng to several of the classical chaperone families, such as heat-shock protein (Hsp)40, Hsp70 and Hsp90, with the 2 main exceptions being the Hsp104 and Hsp60/Hsp10 proteins. The ER also contains chaperones and folding enzymes that are unique, such as calnexin and calreticulin and the family of thiol-disulphide oxidoreductases.
• Hsp40s : 5 ER proteins of the Hsp40 family (DNAJC1 / ERdj1, SEC63 / Erdj2, DNAJB11 / ERdj3, DNAJB9 / ERdj4, DNAJC10 / ERdj-5) are known. They contain a luminally exposed J-domain and can stimulate BiP ATPase activity in vitro
• Hsp70s : the main protein of this family is BiP / hsp70 5 / MIF2 / glucose-regulated protein 78 (GRP78), which takes part in many aspects of ER quality control (QC). It binds to various nascent and newly synthetised proteins and assists their folding. In addition, it is involved in the processes of ER-associated degradation and the unfolded protein response (UPR). The functions of the second Hsp70 family member, glucose-regulated protein (GRP)170, are relatively unexplored.
• Hsp90 : the only known Hsp90 family member is glucose regulated protein, 94 kDa (GRP94) / gp96 / tumor rejection antigen 1 (TRA1) / adenotin. Despite being abundant in the ER, it is not essential for cell viability and seems to limit its interactions to a small set of substrates. Hsp90 is highly conserved, ubiquitous, and one of the most abundant cellular proteins. To date, it has been identified in complexes with over 100 'substrate' proteins, almost all of which reside in the cytosol or nucleoplasm^ref. Humans have two Hsp90 isoforms — Hsp90a and Hsp90b — that are > 85% identical, with little evidence in mammalian cells for functional differences. Trap1 is found in mitochondria and Gp96 is found in the endoplasmic reticulum. Plants also have a chloroplast Trap1.


Hsp70 and Gp96 (the Hsp90-family member from the ER) seem to modulate the immune response by presenting small peptides^ref. In addition, recent evidence has accumulated to indicate that Hsp90 itself can be secreted and may have additional extracellular functions. Vascular smooth muscle cells secrete Hsp90a (not Hsp90b)^ref, and membranes of other cells contain immobile Hsp90 as part of a multimeric lipopolysaccharide (LPS) receptor complex^{ref1, ref2}. Exogenous addition of Hsp90 to culture medium has some cell stimulatory effects. More importantly, antibodies to Hsp90 block LPS signalling^{ref1, ref2} and the activation of prekallikrein on the membrane of endothelial cells^ref. Intriguingly, both MMP2 and prekallikrein are proteases that are made as pro-proteins and require proteolytic activation. The maturation of prekallikrein by HMWK can be promoted by Hsp90 in a purified system^ref. So how does Hsp90 get to the membrane and/or the extracellar space? The known Hsp90 isoforms do not carry recognisable signal sequences that would target them to the secretory pathway or to membranes. However, we cannot exclude the possibility that an alternatively spliced version of Hsp90 contains a secretory signal sequence. Interestingly, the Ensembl.org entry for the human Hsp90 gene points out an alternative transcript with 2 extra exons preceding the standard first exon. Closer inspection reveals that translation initiation at an ATG within the second exon would produce an extended Hsp90 with a predicted N-terminal signal peptide. After its cleavage, the secreted Hsp90 would encompass the entire known Hsp90 sequence with only a 3K N-terminal extension. It is also conceivable that the 'canonical' Hsp90 ends up associated with the outside of cells through an unconventional protein secretion pathway. In the latter scenario, however, one would have to explain why Hsp90b does not follow the same route as Hsp90a. A primarily cytosolic protein such as Hsp90 can be relatively easily pictured as a soluble protein in the extracellular space, but how are we to imagine its membrane association? The exact topology remains to be determined with more detailed analyses. The experiments with the GA-coupled beads suggest that, at the very least, the ATPase domain is close to the surface and is required for MMP2 maturation, although it is noteworthy that Hsp90 is capable of certain ATP-independent chaperone functions^ref. If Hsp90 is both membrane-associated and soluble, which of the two forms is the functional one for a given substrate, say MMP2? A major remaining challenge will be to understand the molecular function of extracellular Hsp90. How does a molecular chaperone, 'accustomed' to the cytosol, work in an oxidative environment with considerably lower ATP concentrations? Perhaps extracellular Hsp90 works less as a chaperone and more as a scaffolding protein, linking to activating proteases for example. A lonely extracellular shift indeed, if it is to function without its usual cohort of co-chaperones^ref, none of which have yet been sighted outside the cell. A loop within the N lobe of the kinase domain of ErbB2 determines Hsp90 binding : the amino acid sequence of the loop determines the electrostatic and hydrophobic character of the protein's surface, which in turn govern interaction with Hsp90. A point mutation within the loop that alters ErbB2 surface properties disrupts Hsp90 association and confers GA resistance. Notably, the immature ErbB2 point mutant remains sensitive to GA, suggesting that mature and nascent client kinases may use distinct motifs to interact with the Hsp90 chaperone complex^ref.
• peptidyl-prolyl isomerases (PPIases) from both of the 2 main PPIase families - the cyclophilins and the FK506-binding proteins (FKBPs) - are found in the ER. Catalysis of cis/trans isomerization of peptidyl-prolyl bonds in vivo remains to be shown conclusively for this proteins.
• calnexin and mobilferrin / calreticulin : these 2 lectin chaperones interacts with and assist the folding of proteins that carry monoglucosylated N-linked glycans.
• thiol-disulphide oxidoreductases : this large family of enzymes, of which protein disulphide isomerase (PDI) / procollagen-proline, 2-oxoglutarate 4-dioxygenase (proline 4-hydroxylase), b polypeptide / thyroid hormone binding protein p55 is the best known, catalyses the oxidation, isomerization and reduction of disulphide bonds.
• low molecular mass heat shock proteins (HSPs) appear to act as molecular chaperones
• HSP20
• HSP27
• alpha B-crystallin
• agranular or smooth endoplasmic reticulum (SER) contains no ribosomes and has no distinctive staining properties
• sarcoplasmic reticulum : a special form of agranular reticulum found in the sarcoplasm of striated muscle and comprising a system of smooth-surfaced tubules forming a plexus around each myofibril
• Golgi apparatus, body or complex / dittiosome : a complex cuplike structure within cells, made up of several elements, each consisting of a number of flattened sacs (cisternae) with associated vacuoles and vesicles. Golgi complexes are membrane sites of the formation of the carbohydrate side chains of glycoproteins and mucopolysaccharides, and of other substances. The secretion vacuoles migrate through the cell membrane and release the glycoproteins and mucopolysaccharides, and thus play a role in internal and external secretion. Cytochemical studies have shown that they are also sites of formation of primary lysosomes and give rise to the acrosome of spermatozoa and the nematocyst of Hydra.
• Golgi's cisternae
• cis Golgi apparatus
• trans Golgi apparatus
• trans Golgi network (TGN)
• vacuole : any small space or cavity formed in the protoplasm of a cell.
• autophagic vacuole / autophagosome / autosome / cytolysosome : an intracytoplasmic vacuole containing elements of the cell's own cytoplasm (autophagocytosis for mitochondria and ER); it fuses with a lysosome to form an autophagolysosome, subjecting its contents to enzymatic digestion
• heterophagic vacuole / heterophagosome : an intracytoplasmic vacuole formed by phagocytosis(heterophagocytosis) or pinocytosis, which becomes fused with a lysosome, subjecting its contents to enzymatic digestion
• condensing vacuoles : membrane-bound spherical vacuoles in the Golgi complex of secretory cells, which contain secretory product in varying degrees of condensation and which mature, pass to the cell surface as secretory granules or droplets, and discharge their contents.
• contractile vacuole / water expulsion vesicle : an osmoregulatory organelle of protozoa and sponges that alternately fills with water extracted from the adjacent cytoplasm and then ejects the water to the outside; thus it acts as a pumping mechanism to remove excess water from the cell.
• food vacuole : a fluid-containing intracytoplasmic space in which food material is suspended; it occurs in holozoic protozoa.
• plasmocrine vacuole : a small cavity containing crystalloids in a secretory cell.
• rhagiocrine vacuole : a small cavity containing colloids in a secretory cell.
• water vacuole : a small drop of water within the protoplasm of a cell.
• intermediate, transfer, transitional or transport vesicles : small vesicles formed by budding off of the granular endoplasmic reticulum, in which secretory material is transferred to the Golgi complex, where it is concentrated in condensing vacuoles
• lysosomes (a.k.a. vacuole in yeasts) : one of the minute bodies seen with the electron microscope in many types of cells, containing various hydrolytic enzymes and normally involved in the process of localized intracellular digestion. Injury to a lysosome is followed by release into the cell of the enzymes, which may damage the cell and give rise to wasting and other pathologic aspects of certain diseases, as in muscular dystrophy.
• primary lysosomes / azurophilic or primary granules : one that has not yet been engaged in digestive activities.
• secondary lysosomes / digestive vacuole : a primary (or another secondary) lysosome that has fused with a phagosome (or pinosome), bringing hydrolases in contact with the ingested material and resulting in digestion of the material
• residual body : a secondary lysosome that has completed its digestive processes but retains indigestible or very slowly digestible material
• multivesicular body : a secondary lysosome manifested as a spherical, membrane-bound vacuole, containing numerous small vesicles in a matrix that exhibits acid phosphatase activity.
• secretory granules : granules in secretory cells that apparently represent material that helps to form the secretion.
• zymogen granules : secretory granules in certain cells, containing the precursors of enzymes that become active after they have left the cell
• specific or secondary granules : a type of neutrophil granule found primarily in mature cells; most are released into the extracellular fluid. They contain lactoferrin, plasminogen activator, leukocyte alkaline activator, and collagenase, as well as membrane-bound molecules that they release onto the cell surface.
• tertiary granules
• microbody : any of the membrane-bound, ovoid or spherical, granular cytoplasmic particles containing enzymes and other substances, which originate in the endoplasmic reticulum of vertebrate liver and kidney cells and other cells, and in protozoa, yeast, and many cell types of higher plants. Two types of microbodies are
• peroxisomes / microbodies : any of the microbodies present in vertebrate animal cells, especially liver and kidney cells, which are rich in the enzymes peroxidase, catalase, D-amino acid oxidase, and, to a lesser extent, urate oxidase; their functions are not fully understood, but they participate in metabolic oxidations involving hydrogen peroxide, purine metabolism, cellular lipid metabolism, and gluconeogenesis
• nucleoid (not to be confonded with nucleoid in Bacteria !) = urate oxidase crystals (not in Aves and Primates)
• glyoxosome / glyoxisome : any of the microbodies present in certain plants and microorganisms, resembling the peroxisomes of vertebrate animal cells, but having, in addition to catalase and oxidase enzymes, the enzymes of the glyoxylate cycle, a metabolic pathway involved in the conversion of fat to carbohydrate. Glyoxosomes, in association with chloroplasts, also participate in the process of photorespiration
• cytoskeleton : a conspicuous internal reinforcement in the cytoplasm of a cell, consisting of tonofibrils, terminal web, or other microfilaments.
• microtubules (13 protofilaments (diameter : 5 nm) made up of a- (ubiquitous, a₁ (testis-specific), a₂, a₃, a₄, a₆, a₈, a-like 1, a-like 3) and b- (b polypypetide, b 2, b₁, b₂, b₃, b₄, b₆, b₈, b polypeptide member Q) tubulin dimers, with minus and plus ends, outer diameter = 25 nm, and inner diameter = 15 nm; also d₁, e₁, and g-tubulin (g₁, g₂). Any of the slender, tubular structures composed chiefly of tubulin, found in the cytoplasmic ground substance of nearly all cells; they are involved in maintenance of cell shape and in the movements of organelles and inclusions, and form the spindle fibers of mitosis. In cilia and flagella, they are constantly arranged with 2 single microtubules in the center and nine pairs of doublets arrayed around the central 2. The atomic structure of tubulin in a polymerized, straight protofilament is clearly distinct from that in a curved conformation bound to a cellular depolymerizer. The nucleotide contents are identical, and in both cases the conformation of the GTP-containing, intra-dimer interface is indistinguishable from the GDP-containing, inter-dimer contact. 2 structures corresponding to the start and end points in the microtubule polymerization and hydrolysis cycles illustrate the consequences of nucleotide state on longitudinal and lateral assembly. In the absence of depolymerizers, GDP-bound tubulin shows distinctive intra-dimer and inter-dimer interactions and thus distinguishes the GTP and GDP interfaces. A cold-stable tubulin polymer with the non-hydrolysable GTP analogue GMPCPP, containing semi-conserved lateral interactions, supports a model in which the straightening of longitudinal interfaces happens sequentially, starting with a conformational change after GTP binding that straightens the dimer enough for the formation of lateral contacts into a non-tubular intermediate. Closure into a microtubule does not require GTP hydrolysis^ref.
• microtubule-associated proteins (MAPs)
• kinesin and its family (KLPs)
• axonemal and cytoplasmic dinein
• tau
• microtubules organizing centers (MTOCs) : they contain the minus end and g-tubulin
• ... in centrosomes or microcenters (or diplosomes if the 2 centrioli are well distinguished) in endoplasm or in ectoplasm : the cell center; the centrosphere together with the 2 centrioles.
• centriole : either of the two cylindrical organelles located in the centrosome and containing nine triplets of microtubules arrayed around their edges; centrioles migrate to opposite poles of the cell during cell division and serve to organize the spindles. They are capable of independent replication and of migrating to form basal bodies. 2 centrioli per centrosome, each made up of 9 peripheral triplets. Each triplet is made up of A (complete: 13 protofilaments), B and C (incomplete: 10 or 11 protofilaments) microtubules : the A microtubule of a triplet is linked to the C microtubule of the adjacent triplet by a nexin bridge. From the A microtubule also arise an inner arm and an outer arm of dinein. The A microtubules are linkedto the center of the centrosome by a ray. During replication steps it is called procentriole
• centriolar DNA
• centrosphere / cytocentrum / microcentrum / attraction sphere / paranuclear body / (peri)centriolar satellites / pericentriolar material (PCM) : specialized area of condensed cytoplasm that contains the centrioles and plays an important part in mitosis as it is the real MTOC
• ...for achromatic (so-called for contrast to chromo-somes !) or mitotic spindle : the spindle is made up of 2 sphere apparatuses, each built up of a diplosome and of an aster or astrosphere. The spindle microtubules are classified in :
• aster microtubules
• chromosomal (or kinetochore) microtubules
• (inter)polar microtubules
• ... in polar bodies of endomitotic spindle (in Fungi)
• ... in basal bodies / kinetosomes / blepharoplasts : 9 peripheral triplets (structured and named as in centriolus)
• ... of cilia : they also contain a basal foot and some radiculae. Ciliar axonema contains 9 peripheral couples (arising from the A and B microtubules of the basal body) + 2 central microtubules (not linked to the basal body). In Platelminta 9+1, in some other Metazoa 9+0 (mobile or not mobile systems).
• procentriole organizer / deuterosome : a cytoplasmic organelle of ciliating epithelial cells that plays a role in the formation of ciliary basal bodies, being the precursor of the procentriole.
• ciliary movement : the lashing motion of cilia occurring in certain of the tissues
• ciliary beat : the rhythmic, coordinated contraction of cilia of cells in a 2-step process involving intraciliary excitation followed by interciliary conduction. The beat may be divided into 2 parts, the effective stroke and the recovery stroke. The rhythm may be either isochronous (all cilia beating simultaneously) or metachronous (beats moving along the cilia in waves).
• cilium pacemaker : the biological regulator which controls the frequency of the beat of the cilia of cells by determining the rate of contraction and excitation.
• kinocilium : a motile, protoplasmic filament on the free surface of a cell
• sliding filament theory : a theory that postulates that contraction of cilia involves a sliding of filaments (microtubules) in a manner comparable to the sliding filament mechanism for the contraction of muscle
• ... of flagella : flagellar axonema contains 9 peripheral couples (arising from the A and B microtubules of the basal body) + 2 central microtubules (not linked to the basal body). In Platyhelmintha 9+1, in some other Metazoa 9+0 (mobile or not mobile systems).
• parabasal apparatus : the structure comprising ..
• parabasal body : a cytoplasmic body of varying appearance, structure, and function closely associated with the nucleus, kinetoplast, and basal body in certain parasitic flagellate protozoa; it is usually connected to the basal body by a fibril or thread, which together are known as the parabasal apparatus. More than one such structure may be present in each organism. Some authorities consider the parabasal body to be the Golgi complex of these cells.
• the fibril or thread that connects it to the basal body
• intermediate filament (about 10 nm diameter)
• myosin I (conventional) and II (unconventional). Myosin II is the predominant class found in muscles and is historically referred to as "conventional" myosin; the other 19 classes are currently referred to as the "unconventional" myosins. The IIB isoform constitutes most of the myosin found in the central nervous system and all of the nonmuscle myosin in the heart : although a conventional myosin, exhibits properties of unconventional myosins like a high duty ratio, resulting from its rapid rate of phosphate release and relatively slow rate of adenosine diphosphate release, and forms smaller filaments
• cytokeratins of tonofilaments
• ... in (hemi)desmosomes
• desmin
• vimentin
• neurofilaments
• light polypeptide
• neurofilament, light polypeptide 68kDa (NEFL)
• neurofilament, light polypeptide-like 1 (NEFLL1)
• neurofilament, light polypeptide-like 2 (NEFLL2)
• heavy polypeptide
• neurofilament, heavy polypeptide 200kDa (NEFH)
• neurofilament, heavy polypeptide-like (NEFHL)
• neurofilament 3 (150kDa medium) (NEF3)
• GFAP
• gigaxonin
• internexin neuronal intermediate filament protein, alpha
• lamin A/C
• lamin B1
• lamin B2
• lamin A/C-like 1
• lamin A/C-like 2
• nestin
• peripherin
• intermediate filament associated proteins
• filaggrin
• plectin
• synamin
• microfilaments (about 7 nm diameter) :
• actin (minus and plus ends, treadmilling)
• actin-binding proteins
• monomer sequestrating proteins
• profilin 1
• profilin 2
• thymosin
• depactin
• dextrin
• ends blocking (capping) proteins
• b-actinin
• capping protein (actin filament), gelsolin-like
• capping protein (actin filament) muscle Z-line, a₁ (CAPZA1)
• capping protein (actin filament) muscle Z-line, a₂ (CAPZA2)
• capping protein a₃
• capping protein (actin filament) muscle Z-line, b (CAPZB)
• crosslinking proteins
• filamin A / ABP280
• filamin B / ABP278
• filamin C / ABP280
• gelactin
• bundle-forming proteins
• plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes
• lymphocyte cytosolic protein 1 (L-plastin) : expressed only in hemopoietic cell lineages
• plastin 3 (T isoform) : hemopoietic cells and other normal cells of solid tissues that have replicative potential (fibroblasts, endothelial cells, epithelial cells, melanocytes, tumors of solid tissues, etc.).
• plastin 1 (I isoform) / fimbrin : expressed at high levels in the small intestine
• villin 1
• villin 2 / ezrin
• villin-like
• supervillin / archvillin
• advillin
• fascin 1
• fascin 2
• fascin 3
• spectrin gene superfamily
• a-actinins : in nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments
• a₁-actinin
• a₂-actinin
• a₃-actinin
• a₄-actinin (nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes)
• a-spectrins
• b-spectrins
• dystrophins
• actin binding LIM protein 1
• actin binding LIM protein 2
• erythrocyte membrane protein band 4.9 (dematin)
• filament-cutting proteins
• fragmin/severin
• gelsolin
• brevin
• membrane-binding proteins
• spectrin family : dystrophin, ...
• ERM (villin 2 / ezrin, radixin and moesin) family : ponticulin, ...
• vinculin
• talin 1
• talin 2
• ... in stereocilium : a nonmotile protoplasmic filament on the free surface of a cell; found on hair cells of the inner ear and on pseudostratified epithelial cells of the male epididymis
• ... in stress fiber :
• ... in terminal web : a feltwork of fine filaments in the cytoplasm immediately beneath the free surface of certain epithelial cells, especially those with a brush border of microvilli, such as the absorptive cells of the intestines and the hair cells of the inner ear; it is thought to have a supportive or cytoskeletal function
• ... in pseudopodium (amoeboid cells) : a temporary cytoplasmic extrusion by means of which an ameba or other ameboid organism or cell moves about or engulfs food. Pseudopodia are of four types
• protopod (on the forefront)
• uropod : the cytoplasmic footlike process that trails behind locomoting leukocytes; the term is used particularly of lymphocytes, in which the trailing process and large nucleus produce a characteristic “hand mirror” shape. The uropod serves as a point of attachment to the substrate and may also be involved in cell-cell interactions
• axopodium / axiopodium : a long and slender (filamentous), semipermanent type of locomotor pseudopodium (no motility function) that has a central axial filament composed of a bundle of microtubules
• centroplast : a central granule from which the axial filaments of the axopodia of certain heliozoa arise
• filopodium : a slender filamentous pseudopodium with a pointed end, branched or unbranched, consisting mostly of ectoplasm
• lobopodium : a wide, blunt (finger-shaped) pseudopodium composed of both ectoplasm and endoplasm
• reticulopodium / rhizopodium : a filamentous pseudopodium with interconnected branches
• acanthopodium : anastomized finger-shaped pseudopodia
• ... in lamellipodium : delicate sheetlike extensions of cytoplasm which form transient adhesions with the cell substrate and wave gently, enabling the cell to move along the substrate.
• ... in microspike
• invadopodia are convolutions and extensions of the ventral plasma membrane that contacts the substratum. These structures represent specific sites where degradation of the underlying matrix occurs, and might also be secretory sites to which nascent protease-containing carriers are targeted for release. Invadopodia are prominent in cells that actively migrate and invade surrounding tissues, such as metastatic tumour cells.
• podosomes, which are less well defined than invadopodia, are also formed along the cell base. These structures share many components and features with invadopodia and might represent a modification of invadopodia in cells that are cultured on an artificial substrate such as glass.
• circular dorsal ruffles/waves are formed on the dorsal surface of cells after stimulation of receptor tyrosine kinases including the epidermal growth factor receptor or the platelet-derived growth factor receptor. Circular dorsal ruffles/waves use many of the same components as invadopodia and podosomes, but are transient, appear to reorganize the surrounding actin cytoskeleton, and might have an endocytic function as opposed to a secretory one.
Reorganization of cortical actin filaments plays critical roles in cell movement and pattern formation. Recently, the WASP and WAVE family proteins WASP and N-WASP, and WAVE1, WAVE2 and WAVE3 have been shown to regulate cortical actin filament reorganization in response to extracellular stimuli. These proteins each have a verprolin-homology (V) domain, cofilin-homology (C) domain and an acidic (A) region at the C-terminus, through which they activate the Arp2/3 complex, leading to rapid actin polymerization. N-WASP is usually present as an inactive form in which the VCA region is masked. Cooperative binding of Cdc42 and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P₂) exposes the VCA region, activating N-WASP. In addition to this activation mechanism, WISH also activates N-WASP independently of Cdc42 and PtdIns(4,5)P₂, by binding to the proline-rich region of N-WASP. N-WASP activation induces formation of filopodia in vivo. In contrast, the ubiquitously expressed form of WAVE2 is activated downstream of Rac, leading to formation of lamellipodia. In this case, IRSp53 transmits a signal from Rac to WAVE2 through formation of a ternary Rac-IRSp53-WAVE2 complex. Thus, N-WASP, which is activated downstream of Cdc42 or independently by WISH, induces formation of filopodia and WAVE2, which is activated via IRSp53 downstream of Rac, induces formation of lamellipodia.
Bibliography :
• Nature Insight Cytoskeleton in Nature Vol.422 17 April 2003
Web resources : The cell biology and cytoskeleton group of the division of hematology at Harvard Medical School
• nematodesma / trichite : a bundle of parallel microtubules serving to support the cytostome and cytopharyngeal apparatus and associated organelles of certain ciliate protozoa; also seen in certain flagellate groups
• cytopharynx : a nonciliated gullet-like canal between the cytostome and the endoplasm of ciliate and certain other protozoa
• cytopharyngeal apparatus : a cytopharynx with walls supported by nematodesmata
• rhabdos : a straight cytopharyngeal apparatus with walls supported by nematodesmata and sometimes containing toxicysts; it is characteristic of the lower ciliate protozoa
• cytostome : the mouth opening of ciliates and certain other protozoa, which opens into the cytopharynx, which in turn opens into the endoplasm.
• axostyle : a filamentous or hyaline-supporting structure passing through the longitudinal axis of certain flagellate protozoa, such as trichomonads, and sometimes extending beyond the posterior end of the organism. Its enlarged capitulum may give rise to or be covered by a pelta.
• cell inclusion : a usually lifeless (metabolically inactive), often temporary, constituent of the cytoplasm of a cell, such as an accumulation of proteins, fats, carbohydrates, pigments, secretory granules, crystals, or other insoluble components.

granules : insoluble nonmembranous particles found in cytoplasm

albuminous or cytoplasmic granules : granules seen in the cytoplasm of many normal cells; they optically disappear on the addition of acetic acid, but are not affected by ether or chloroform

Kölliker's interstitial granules : various sized granules seen in the sarcoplasm of muscle fibers.

paraplasm

glycogen granules

pigments in pigment granules (small masses of coloring matter occurring in pigment cells)

aleuronoid granules : colorless myeloid colloidal bodies found in the base of pigment cells.

lipochromes

lipofuscin / lipofuchsin : wear and tear pigment (in residual bodies)

bilirubin

hemosiderin = ferritin granules

melanin : the dark amorphous pigment of the skin, hair, and various tumors, of the choroid coat of the eye and the substantia nigra of the brain. It is produced (melanogenesis) by polymerization of oxidation products of tyrosine and dihydroxyphenyl compounds, and contains carbon, hydrogen, nitrogen, oxygen, and often sulfur

pheomelanins (melanosomes in melanocytes => keratinocytes)

eumelanins / black melanins (melanosomes in melanocytes => keratinocytes)

neuromelanins (neurons in the substantia nigra of Sommering and retinal pigment epithelium)

melanogen : a colorless chromogen, convertible into melanin, which may occur in the urine in certain diseases, e.g., malignant melanoma..

artificial or factitious melanin / melanoid : a compound resembling melanin, formed when a protein is heated in strong hydrochloric acid

crystals : a homogeneous angular solid formed from a chemical element, compound, or isomorphous mixture, having a definite form in which the ultimate units from which it is built up are systematically arranged

• crystalloid : resembling a crystal

Charcot-Böttcher crystalloids : slender spindle-shaped crystals 10 to 25 m long, commonly found in Sertoli cells of the human testis but not in other species

crystalloids of Reinke : conspicuous, variously shaped, crystal-like structures contained in the cytoplasm (and rarely in the nucleus) of interstitial cells of Leydig.

• ferritin crystals : in Insects enterocyte, where hemosiderin can crystallize
• guanine crystals (in Amphibia keratinocytes)
• nucleoid (see peroxisome)

• diffusible signals
• gap junctions
• ultrafine F-actin-based horizontal cellular extensions that make cell-to-cell contacts
• cytonemes : in wing imaginal disc cells in Drosophila that project to a signaling center associated with the anterior/posterior compartment border. Cytonemes can be induced when cells from the lateral flanks of a wing disc are cultured next to cells from the A/P border or next to a source of fibroblast growth factor. Mouse limb bud cells also grow projections during a brief culture period, indicating that cytonemes are an attribute of both vertebrate and invertebrate cells. Cytonemes may be responsible for some forms of long-range cell-cell communication.
• tunneling nanotubes (TNTs) : swimming in the media and not attached to the substrate in cultured cells. They have diameters of 50 to 200 nm, lengths up to several cells long, contain F-actin and facilitate organelle transport between cells^{ref1, ref2}

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