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mcb1 17 Posttrans 2023

The document discusses various posttranslational modifications (PTMs) of proteins, including N-terminal, C-terminal, and internal modifications such as phosphorylation, glycosylation, and acetylation. It highlights the significance of these modifications in protein function, stability, and interactions, as well as their roles in processes like blood clotting and collagen formation. The document emphasizes that PTMs are combinatorial and their effects depend on the specific combinations present on proteins.

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5 views27 pages

mcb1 17 Posttrans 2023

The document discusses various posttranslational modifications (PTMs) of proteins, including N-terminal, C-terminal, and internal modifications such as phosphorylation, glycosylation, and acetylation. It highlights the significance of these modifications in protein function, stability, and interactions, as well as their roles in processes like blood clotting and collagen formation. The document emphasizes that PTMs are combinatorial and their effects depend on the specific combinations present on proteins.

Uploaded by

camosundental
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Posttranslational modifications

SEMMELWEIS UNIVERSITY

Department of Molecular Biology


at the Institute of Biochemistry and Molecular Biology

Tamás Mészáros
Nat Rev Genet. 2009 Oct; 10(10): 715–724.
Location of posttranslational modifications

N-terminal C-terminal

Internal
N-terminal modifications

Methionine cleavage

Acetylation

Cotranslationally
80-90% of eukaryotic proteins

Myristoylation
C-terminal modifications

Amidylation

Typical for peptide hormones (endorphins)


Cholesterylation

Glycosylphosphatidylinositol coupling

C terminal, hydrophobic peptide signals GPI coupling. GPI


tethers proteins on the cell surface.
Modifications of internal
amino acids

Acetiláció
Diszulfidhíd
Foszforiláció
Glikolizáció
Hidroxiláció
Metiláció
Palmitoiláció
Preniláció
SUMO-lizáció
Szulfatáció
Ubikvitináció

There are only few examples for Ile, Leu, Val,


Ala, Phe modfications
Hydroxylation
ER

Hydroxylation of proline >> hydrogen bonds in collagen triple helix


Lysine deamination

Norleucin

Lysinonorleucin cross-linking

Collagen are covalently cross-linked as well.


Number of covalent bonds increases with ageing.
Prolyl hydroxylase

Fe2+ >> Fe3+

Reduction of Fe3+ is vitamin C dependent


Tethering membrane proteins

https://doi.org/10.1016/j.pbiomolbio.2017.01.002

Prenylation: Phosphatidylethanolamidation: GPI coupling


C-terminal Cys Serine C-terminal
Farnesyl-OPP, LC3 protein is the only protein (e.g. AChE)
geranylgeranyl-OPP (autophagy)
(e.g. Ras)
Myristoylation: Palmitoylation: Cholesterylation:
N-terminal Gly Internal Cys or Ser C-terminal
Myristoil-CoA Palmitol-CoA carboxyl-group
(e.g. PKA) (e.g. Ras) (e.g. Hedgehog)
Ca2+ binding by carboxylation

Indispensable for blood clotting


Vitamin K dependent, in ER
Modification results in increased calcium binding capacity
Protein phosphorylation

The most general modification


Very fast, highly specific and reversible process
Phosphorylation results in conformational change

Glycogen phosphorylase
Tense and Relaxed
conformation

Ser14 Ser14-P
More than 500 human protein kinase
and 150 protein phosphatase
More than 100 substrate of a single kinase
(PKA) have been described
There could be many phosphorylation sites on proteins
Glycosylation

Mostly the extracellular and membrane proteins are glycosylated


O-Glycosilation: ~10%, on serine or threonine, in the Golgi
N-Glycosilation: ~90%
On asparagine of Asn-X-Ser or Asn-X-Thr motifs
A common five carbohydrate composed structure,
Modification starts in the ER and goes on in the Golgi
Proteoglycans

60-95% of the molecule is carbohydrate


Negative charge draws Na+ hydrate shell flexibility
Composition of all N-glycosylated proteins starts with
attachment of identical carbohydrate block.
The coupled block is extensively modified in ER and Golgi

The proteins are identically decorated by carbohydrates

23 MARCH 2001 VOL 291 SCIENCE


Functions of glycosylation:
Protecting proteins from degradation
Selective labelling of proteins
Determines cell-cell connections
Essential in protein folding quality control
Regulation of transcription

Methylation

Increasing hidrophobicity
Chromo (Chromatin Organization Modifier)
domain motif, heterochromatin formation
Vitamin C is a needed cofactor of histone
demethylation
Acetylation

deacetylase
acetylase
Histone

Histone

Charge change
Bromo domain motif
Hundreds of modifications at the N-terminal of histones create
the histone code

•DOI: 10.1517/14728222.12.10.1301

https://doi.org/10.1038/s41576-022-00468-7
The histone code is interpreted by modification specific protein domains

More than 80 protein domains are dedicated for


identifaction of PTMS

https://www.med.unc.edu/~bstrahl/research.html

http://pawsonlab.mshri.on.ca

Posttranslational modifications determine


protein-protein interactions
Three components of the posttranslational modification system

https://doi.org/10.1515/hsz-2018-0458

Histone acetylase Histone deacetylase Modification specific domains


The PTMs are combinatorial

p53

The modifications must not be considered as


isolated events,
their outcome is determined by the
combination of the various modifications

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