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| Intrachain (with no prosthetic group) | every amino acid in the chain (also not contiguous) | intrachain disulfide bond in globular preproprotein | RNAase, insulin ,
Ig |
2 Cys => cystin | usually uncatalyzed, except for protein disulfide isomerases (PDI) |
| deamidation | CaM
HIF-1a |
Asn + H2O => isoAsp or D-Asp + NH4+
Gln + H2O => Glu + NH4+ |
gGT
TGM2 |
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| thyronin formation | thyroglobulin | DIT + MIT (or DIT) => dehydroAla + (r)T3 (or T4) | uncatalyzed (hypothetical role for TPo
?) |
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| isomerization | PIN1 | Pro | peptidyl-prolyl cis-trans isomerase (PPI) | ||
| dehydratation | Asp => dehydroAsp
Ala => dehydroAla |
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| oxidation | SERCA1,
SERCA2a,
CaM,
b-amyloid,
collagen,
elastin |
Cys => Cya
Met => Met sulphoxide Lys, Pro, Arg, Thr => aldehyde and ketons |
R.O.S. <=> Msr
Lys oxidase |
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| N-terminal amino acid | cyclization | neurotensin,
TSH,
TRH,
GnRH |
Glu => pyroGlu or 5-oxoPro or Glp | ||
| C-terminal amino acid | cyclization | Hse => Hsl | |||
| Intrachain with covalently bound
prosthetic groups :
1) as coenzymes |
every amino acid in the chain | thiamine PP |
? | ||
| FMN / FAD |
e-Lys amide (other ?) | ||||
| ACP | e-Lys amide | ||||
| PyP | Schiff's base with e-Lys | ||||
| biotin |
e-Lys amide | ||||
| 5'dA-B12 |
? | ||||
| methyl-B12 |
? | ||||
| rhodopsin |
Schiff's base with e-Lys | ||||
| naphtoquinone | ? | ||||
| lipoic acid | e-Lys amide | ||||
| heme c | 2 Cys | ||||
| heme P460 | 2 Cys | ||||
| 2) in conjugated proteins with no enzymatic activity | every amino acid in the chain | cotranslational N-glycosylation in ER and Golgi apparatus | Asn in NX(no P)S/T box => 1st sugar GlcNAc | specific glycosyltransferase and UDP-, GDP- or CMP-sugars | |
| O-glycosylation in Golgi apparatus (via dolichol phosphate) | collagen |
Ser, Thr 5-Hyl => 1st sugar GalNAc | |||
| diphtamidation | eEF2 | NtHis | Corynebacterium
diphteriae toxin |
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| methylation = charge neutralization | CheR, CaM, cyt c, H3 | Glu, Asp, Lys, Nt/pHis, Arg | specific methyltransferase and S-AdoMet | ||
| acetylation (C2) = charge neutralization | a-tubulin, H2A, H2B, H3, H4 | Lys + acetylCoA | histone acetyltransferase
(HAT)
and histone deacetylase
(HD or HDAC) |
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| palmytoylation (C16) | some GPCRs' CTD |
=> Cys thioester | |||
|
isoprenylations or terpenylations [cytosol-side anchors]
=> direction to cellular membranes and protein-protein interactions
|
farnesylation (C15) | Ras familyref1,
ref2,
ref3,
g-subunit
of some heterotrimeric G proteins (e.g. transducins) |
attachment of the prenyl moiety to the cystein
resiude of the carboxy-terminal CAA(aliphatic, no Ala)X(preferably Ser
or Met) motif by protein farnesyl
transferase (FTase)ref1,
ref2
or protein
geranylgeranyltransferase-I (GGTase-I), respectively. Folowing the
attachment of the isoprenoid, the AAX tripeptide is removed in a reaction
that is catalysed by a prenyl-protein-specific protease known as RCE1ref,
whereas in the third processing step a methyl group is transferred to the
now C-terminal prenylcysteine by the enzyme isoprenylcysteine
carboxyl methylatransferase (ICMT) (activation !) => Cys thioether |
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| geranylgeranylation (C20) | CDC42, g-subunit
of some heterotrimeric G-proteins,
RHO family (which includes RAC and CDC42), RAB family, RAC family, RAP
family
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|
nucleotidylations
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adenilylation | Gln synthetase | Ser-, Thr-, Tyr-OH | ||
| uridilylation | PII | Ser-, Thr-, Tyr-OH | |||
| mono-(in Prokarya) or poly-(in Eukarya) ADP-ribosylation | H1,
G-protein as
and ai-subunit,
eEF2, Rho CTCF-like (CTCFL) |
Asn, Nt-diphtamideHis, Arg | PARP,
Vibrio cholerae
toxin (+ARF),
Corynebacterium diphteriae
toxin,
Pseudomonas aeruginosa
toxin,
Clostridium botulinum
toxin,
Bordetella pertussis
toxin,
Escherichia coli
LT toxin |
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| hypusination | eIF5A / eIF4D | Lys + butylamino group from spermidine (=> putrescine) + OH- => hypusine | |||
| sulphonation | fibrinopeptides, chromogranin
B, gastrin II or 17,
CCK |
Tyr-OH | specific sulphotransferase and PAPS (irreversible !) | ||
| nitrosylation | RYR,
glutathione |
Cys + NO. => Cys-S-N=O | uncatalyzed | ||
| nitration | SERCA2a | Tyr + ONOO- => 3-nitro-Tyr | uncatalyzed | ||
| carboxylation | osteocalcin
factor II factor VII factor IX factor X GAS6 matrix Gla protein protein C protein S protein Z PRGP1 PRGP2 TMG3 TMG4 |
Glu => Gla (Ca2+ chelating !) | g-glutamyl
carboxylase |
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| halogenations | thyroglobulin | Tyr + I2 => MIT (or DIT) | uncatalyzed (hypothetical role for TPo
?) |
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| phosphorylation | many proteins ! | Ser/Thr-, Tyr-, Hyp-, His-, Asp-OH | specific protein kinases (sometimes autophosphorylation occurs !) and
phosphatases
The discovery in the 1940s and 50s that adding a phosphate group can change a protein's activity won its discoverers, Edmond Fischer and Edwin Krebs, a Nobel prize in 1992. Instead of ATP, Snyder and his team propose that a molecule called IP7 transfers one of its 7 phosphate groups to another protein, without the help of an enzyme. To demonstrate this, they radioactively tagged one of the phosphates on IP7, before mixing it with a slurry of proteins extracted from yeast, mice or flies. They showed that the radioactive phosphate wound up attached to a plethora of other proteins, and went on to identify a handful of themref. |
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| cotranslational hydroxylation | collagen type I
and type II
HIF-1a |
Lys => 5-Hyl (=> glycosylation)
Pro => 3- or 4-Hyp, Asp, Asn |
specific ER hydroxylase :
+ aKG + vitamin
C
=> CO2 + succinate + hydroxy-Xaa (more hydrogen bonds !) |
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| N-terminal amino acid | formylation | all proteins in Bacteria | Met (pretranslational in Bacteria !) | Met-tRNAMet transformylase and peptide deformylase | |
| methylation | fimbrial protein in Neisseria, Pseudomonas and Vibrio spp. | Phe | ? | ||
| acetylation | H1, H4 | Ser | cytosolic histone
acetyltransferase (HAT)
: irreversible ! |
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| miristoylation [cytosol-side anchor] | C subunit of PKAs, a subunit of G proteins, c-Src SH4 domain | Gly | |||
| carboxylation | Hb and other serum proteins | Any | uncatalyzed => Hb carbammates | ||
| C-terminal amino acid | PE-amide | Apg8 | Gly | Apg4 | |
| primary amide | a-MSH,
secretin0
gastrin II or 17 ,
CCK,
GHRH ,
CRH ,
oxytocin ,
ADH,
GnRH,
chromogranin
A,
TSH ,
TRH,
calcitonin,
substance P |
Val
Phe Leu Ala Gly Pro
|
-NH2 donor = Gly
cofactor = vitamin C |
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| glypiation [GPI ECM-side anchor] | AChE,
AlkP, CD14 / LPS-R, CD16b / FcgRIIIB, CD24 / BA-1 / HSA, CD48 / BCM1 / Blast-1 / Hu Lym3 / OX-45, CD55 / DAF, CD56 / NCAM, CD58 / LFA-3, CD59 / 1F-5Ag / H19 / HRF20 / MACIF / MIRL / P-18 / Protectin, CD67, CD73 / 5'-nucleotidase, CD87 / uPAR, CD90 / Thy-1, CD230 / PrP |
Gly, Asp | -COO-ethanolamine
-phosphate-Man- Man-Man- GlcNAc-Ins-PA |
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| methylation | PP2A |
Leu | |||
| Anabolic partial proteolysis | N-terminal amino acid(s) | fMet and other amino acid(s) removal | many proteins | many amino acids | aminoexopeptidases => t1/2 variation |
| signal sequence removal from preproteins or from preproproteins | preproinsulin
preprocollagen |
signal recognition particle (SRP) (9 kDa, 14 kDa / homologous Alu RNA binding protein, 19 kDa, 54 kDa, 68 kDa, 72 kDa) and signal peptidase (12 kDa and 18 kDa) | |||
| inactivating sequence removal from proproteins | zymogens/proenzymes, prohormones, fibrin
(fibrinopeptides), NFkB,
collagen
(telopeptides) |
endopeptidases (telopeptidase, ...) | |||
| creation of different proteins from a polyprotein | POMC,
prodynorphin,
protachykinin,
ubiquitin/S?, gag-pol,
dentin
syalophosphoprotein (DSPP) |
Ub C-terminal hydrolase, Pro, ... | |||
| creation of more copies of a same protein from a polyprotein | poliUb | Ub C-terminal hydrolase | |||
| protein splicing | Hedgehog homologs |
intein removal and extein splicing | |||
| peptide bond hydrolysis with no contiguity alteration thanks to disulfide bond(s) | thrombin,
insulin,
insulin
receptor,
Clostridium
botulinum
neurotoxin |
endopeptidases | |||
| Olygomers formation | bond between 2 chains | interchains disulfide bond | Ig |
2 Cys => cystin | uncatalyzed (except for protein disulfide isomerase or PDI) |
| lysylnorleucinylation | collagen,
elastin |
Lys + oxidized Lys => LysNle | |||
| desammonification | fibrin |
Gln + e-Lys => NH4+ + ? | transglutaminase/factor XIII | ||
| bond among till to 4 chains | His merodesmosin formation | collagen |
Lys + 2 oxidized Lys + His => His-meroDes | ||
| desmosin and isodesmosin formation | elastin |
Lys + 3 oxidized Lys => Des or isoDes | |||
| Olygopeptide addition | mono- (<4) or poly- (>/=4) ubiquitylation
or ubiquitination (= ubiquitin (UB) A,
B,
C
or
D
addition)
In polyubiquitinylation E3s mediate isopeptidic bonds between a target-bound-Ub e-Lys and the -OOC-Gly of another target-bound Ub molecule. The e-Lys in the first Ub molecule may be K11, K29, K48 (=> 26S proteasome, except for p21CIP1/WAF1 and ornithine decarboxylase (ODC), for which an antizyme system (OAZ1, OAZ2, OAZ3, and inhibitor) occurs) or K68 (=> DNA repair, IKK) |
intra chain e-Lys (N-terminal
amino acid for MyoD1
ubiquitylation !) + Ub => isopeptidic bond
E1s (ubiquitin-activating ATPase) E2s/UBCs (carrier) : Ubc7 in S.cerevisiae, UBE2G1 and UBE2G2 in humans E3s :
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mono-UBLations
(no Ks on UBLs for isopeptidic bonds between them !)
|
sumoylation (= SUMO1/sentrin addition) | H4
If on the same Lys residues used for ubiquitylation, sumoylation prevents
it ! If on other K it may stabilize or address the target
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| rubylation (= Rub1/Nedd8 addition) | Apg8 (reversible)
Apg12 (irreversible) |
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| neddylation, the process that conjugates the ubiquitin-like polypeptide Nedd8 to the conserved lysines of cullins, is essential for in vivo cullin-organized E3 activities. Cullin family proteins organize ubiquitin ligase (E3) complexes to target numerous cellular proteins for proteasomal degradation. Deneddylation, which removes the Nedd8 moiety, requires the isopeptidase activity of the COP9 signalosome (CSN)3, 4. In cells deficient for CSN activity, cullin1 (Cul1) and cullin3 (Cul3) proteins are unstable, and that to preserve their normal cellular levels, CSN isopeptidase activity is required. Neddylated Cul1 and Cul3 are unstable — as suggested by the evidence that Nedd8 promotes the instability of both cullins — and that the unneddylatable forms of cullins are stable. The protein stability of Nedd8 is also subject to CSN regulation and this regulation depends on its cullin-conjugating ability, suggesting that Nedd8-conjugated cullins are degraded en bloc. While Nedd8 promotes cullin activation through neddylation, neddylation also renders cullins unstable. Thus, CSN deneddylation recycles the unstable, neddylated cullins into stable, unneddylated ones, and promotes cullin-organized E3 activity in vivoref. | |||||
| Aminoacylation | N-terminal aminoacid | arginylation | |||
| amide bonds to e-amino group of Lys | N-homocysteinylation | fibrillin 1 | spontaneous | ||
| PEGylation | to couple PEG to a protein, it is first necessary to activate the polymer by converting the hydroxyl terminus to a functional group capable of reacting typically with lysine and N-terminal amino groups of proteins. Each ethylene oxide unit of PEG associates with two to three water molecules, which results in the molecule behaving as if it were five to ten times as large as a protein of comparable molecular weightref. The clearance rate of PEGylated proteins is inversely proportional to molecular weight. Below a molecular weight of approximately 20,000, the molecule is cleared in the urine. Higher-molecular-weight PEG proteins are cleared more slowly in the urine and the fecesref | synthetic PEG addition ! =>
increased serum half-life and reduced antigenicityref, enhanced solubility, decreased proteolysis, and reduced rates of kidney clearance as well as enhanced selective tumor targeting : |
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