ptm

Faculty of Science

Co- and Post-translational Modifications Based on:

Expasy FindMod Documentation
T.E. Creighton, Proteins: structures and molecular principles, 2nd ed. p. 69, W.H. Freeman, 1993
Matthias Mann & Ole N. Jensen, Proteomic analysis of post-translational modifications, Nature Biotechnology 21, 255 - 261 (2003) (Table 1)
Nalivaeva NN, Turner AJ., Post-translational modifications of proteins: acetylcholinesterase as a model system. Proteomics. 2001 Jun; 1(6): 735-47.

Modifications Sorted by Name
(Concise description)

Modifications Sorted by Target Amino Acids
(Names only)

PTM Type	Kingdom	Residues	Position	Rule	Function & Notes
Acetylation	All All very common in eukaryotes and rare in prokaryotes	not N,K,R,H,F,W,Y K	N-terminus Anywhere	- -	One of the most common modifications. Regulates protein stability and protein-DNA interactions (via acetylation of histones) and thus affects transcription. (Acetyl-coA is a required co-factor). Acetylation of N-term occurs in the cytoplasm.
Alkylation	Metazoa	C, H, (K)	-	-
Amidation	Eukaryotes	All	C-terminus	Needs a G after C-terminus on precursor	Amidation of alpha-CO2H occurs in secretory vesicles and granules.
Beta-methylthiolation	E.Coli	D	Anywhere	-
Carbamylation	All	All K	N-terminus Anywhere	- -
Citrullination	Mammalia	R	Anywhere	-
C-Mannosylation	Eukaryotes	W	Anywhere	-
Cysteine sulfenic acid (-SOH)	Metazoa, Bacteria, Plants?	C (side chain)	-	-
Cysteine sulfinic acid (-SO2H)	Metazoa, Bacteria, Plants?	C (side chain)	-	-
Cysteine disulfide bond formation	Prokaryotes Eukaryotes	C	Anywhere		Cysteine disulfide bond formation occurs in the periplasmic space of bacteria and in the ER of eukaryotes.
Deamidation	All All	N Q	Anywhere Anywhere	Needs to be followed by a G -	Possible regulator of protein-ligand and protein-protein interactions.
N-acyl diglyceride cysteine (tripalmitate)	Prokaryotes, Archaebacteria, Phages	C	N-terminus after cleavage of signal peptide	Prosite PDOC00013 Consensus pattern: {DERK}(6)-[LIVMFWSTAG](2)-[LIVMFYSTAGCQ]-[AGS]-C [C is the lipid attachment site] Additional rules: 1) The cysteine must be between positions 15 and 35 of the sequence in consideration. 2) There must be at least one Lys or one Arg in the first seven positions of the sequence.
Farnesylation	Eukaryotes, Viruses	C	Anywhere	-	Membrane tethering, reversible
Formylation	All	All	N-terminus	-
Geranyl-geranyl	Eukaryotes, Viruses	C	Anywhere	-
Gamma-carboxyglutamic acid	Eukaryotes	E	Anywhere	-
N-linked Glycosylation	Eukaryotes	N, Q	Anywhere	-	Found in secreted proteins, involved in cell-cell recognition. Core glycosylation of Asn occurs in the ER. Modification of N-glycosyl groups occurs in the Golgi aparatus.
O-linked Glycosylation	Eukaryotes	S, T, (N)	Anywhere	-	O-glycosylation with GalNAc (N-acetylgalactoseamine) occurs in the Golgi apparatus. O-glycosylation with GlcNAc (N-acetylglucoseamine) occurs in the cytoplasm and in the nucleus, is reversible and has regulatory functions.
Glucosylation (glycation)	All All	All N, T, K	N-terminus Anywhere	- -
Glutathionylation	Metazoa, Bacteria	C (side chain)	-	-
Hydroxylation	Eukaryotes	P,K,D,N	Anywhere	-	Hydroxylation of procollagen Pro and Lys residues occurs in the ER.
Methylation	All	All	Anywhere	-	Regulation of gene expression (via histones methylation).
Myristoylation	Eukaryotes, Viruses Eukaryotes	G G K	N-terminus N-terminus Anywhere	-	Myristic acid is co-translationally attached to gly in the seq: N-term met-gly following the cleavage of met. Many signalling proteins are N-myristoylated. Myristoylation is often required for membrane binding of proteins. Myristoylation alone is not enough - a second modificition is normally required to stabilise membrane association. Phosphorylation of the myristoylated protein can destabilise the interaction, releasing the protein from the membrane. Myristoylation occurs in the cytoplasm.
N-Octanoate	Mammalia	S: N-Octanoate group linked through an ester bond to a serine residue	Anywhere	-
Palmitoylation	Eukaryotes	C (S,T,K)	Anywhere near N- or C- termini or close to transmembrane domains.	-	Cellular localization and targeting to membrane (stabilises myristoylation). A reversible process. May also be involved in stabilising against protein turnover and/ or delivery to lysosomes. Palmitoylation occurs in the cytoplasm or in the ER.
Phosphorylation	Eukaryotes, Viruses Prokaryotes	S,T,Y,H,D S,T,Y,H,C,D	Anywhere	-	Reversible, activation/ inactivation of enzyme activity. Regulation of transcription via phosp. of histones.
Prenylation	Eukaryotes	C	C-terminus	CAAX box = cysteine, 2x any aliphatic aa, any aa. The nature of X determines whether farnesylation or geranylgeranylion occurs. The addition of the prenyl group to C is followed by proteolytic removal of the AAX sequence and carboxylmethylation of the C-term C. (This step occurs in the endoplasmic reticulum)	Addition of a 15- carbon farnesyl group or a 20- carbon geranylgeranyl moiety. ~ 2% of eukaryotic proteins exist in prenylated form. Prenyl proteins have relatively short half- life (~20 hrs), and their turnover requires removal of the C-prenyl moiety.
Sumoylation	Eukaryotes	K		Most SUMO-modified proteins contain the tetrapeptide motif B-K-x-D/E where B is a hydrophobic residue, K is the lysine conjugated to SUMO, x is any amino acid (aa), D or E is an acidic residue.	MW of Sumo-1 is ~ 11 KDa. Related to protein import to the nucleus
Sulfation	Eukaryotes	Y	Anywhere	PROSITE PDOC00003	Modulation of protein-protein and receptor-ligand interactions. Sulafation occurs in the Golgi apparatus.

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Modifications Sorted by Amino Acids

Modifications Sorted by Localization: Side Chains vs. Peptide Chain

Modifications on Peptide Chain	Modifications on Side Chain
proteolytic cleavage, rearrangement, inversion (inteins), N- and C-terminal modification	Phosphorylation, acylation, prenylation, O- and N- glycosylation, nucleosidylation, di sulfide formation, methylation, hypusine, vitamin K dependent carboxylation, hydroxylation, cross-links, etc

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Additional Reading

General

Lothrop AP et. al., Deciphering post-translational modification codes, FEBS Lett. 2013 587(8):1247-57
Walsh G., Post-translational modifications of protein biopharmaceuticals. Drug Discov Today. 2010 Sep;15(17-18):773-80
Han KK, Martinage A., Post-translational chemical modification(s) of proteins. Int J Biochem. 1992; 24(1): 19-28.
Han KK, Martinage A., Post-translational chemical modifications of proteins--III. Current developments in analytical procedures of identification and quantitation of post-translational chemically modified amino acid(s) and its derivatives. Int J Biochem. 1993 Jul; 25(7): 957-70.
Post-Translational Modification.
Lecture 7 Post-Translational Processing .

Disulfide Bond Formation

Feige MJ, Hendershot LM., Disulfide bonds in ER protein folding and homeostasis, Curr Opin Cell Biol. 2011 Apr;23(2):167-75
Fomenko DE, Gladyshev VN., Genomics perspective on disulfide bond formation. Antioxid Redox Signal. 2003 Aug;5(4):397-402.
Frand AR, Cuozzo JW, Kaiser CA., Pathways for protein disulphide bond formation. Trends Cell Biol. 2000 May;10(5):203-10.
Kadokura H, Katzen F, Beckwith J., Protein disulfide bond formation in prokaryotes. Annu Rev Biochem. 2003;72:111-35. Epub 2003 Jan 09.

Phosphorylation in Prokaryotes

Kennelly PJ, Archaeal protein kinases and protein phosphatases : insights from genomics and biochemistry, Biochem. J. 2003; 370: 373-389
Kennelly PJ., Protein kinases and protein phosphatases in prokaryotes: a genomic perspective. FEMS Microbiol Lett. 2002 Jan 2;206(1):1-8.
Leonard CJ, Aravind L, Koonin EV., Novel families of putative protein kinases in bacteria and archaea: evolution of the "eukaryotic" protein kinase superfamily. Genome Res. 1998 Oct;8(10):1038-47.

Glycosylation

Essentials of Glycobiology (Pubmed books section) Later edition (2009)
Nature Insight: Glycochemistry & Glycobiology (2007)
Essentials of Glycobiology Course
Baker JL, Çelik E, DeLisa MP., Expanding the glycoengineering toolbox: the rise of bacterial N-linked protein glycosylation. Trends Biotechnol. 2013 May;31(5):313-23

Sumoylation

Yang XJ, Chiang CM., Sumoylation in gene regulation, human disease, and therapeutic action. F1000Prime Rep. 2013 Nov 1;5:45
Seeler JS, Dejean A., Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol. 2003 Sep; 4(9): 690-9.

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