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tisdag 2 juli 2019

SENP proteiinit, desumoylaasit , Sentriinispesifiset proteaasit.

https://www.ncbi.nlm.nih.gov/pubmed/18666185/

Abstract

Modification of proteins by ubiquitin and SUMO (small ubiquitin-like modifiers) is a dynamic and reversible process. Similar to the ubiquitin pathway, where the action of deubiquitinating enzymes (DUBs)  removes ubiquitin from ubiquitin-adducts, SUMO is also removed intact from its substrates by proteases belonging to the sentrin-specific proteases (SENPs) family. In addition to their isopeptidase activity, SENPs also execute another essential function as endopeptidases by removing the short C-terminal extension from immature SUMOs. The defining characteristics of SENPs are their predicted conserved molecular scaffold-defined as members of peptidase Clan CE, conserved catalytic mechanism, and their reported activity on SUMO or Nedd8 conjugated proteins (or the respective precursors). We discuss recent progress on the human SENPs and their substrates.
PMID:
18666185
DOI:
10.1002/iub.113
INTRODUCTION.  Protein modification by small ubiquitin‐like modifiers (SUMOs) regulates the function, fate, and subcellular location of a growing number of cellular proteins. SUMOylation is often a prerequisite or a competitor for ubiquitination, and therefore influences the degradation of polyubiquitinated proteins (1). Consequently, the regulation of SUMOylation is considered important in the ultimate disposal or aggregation of subsets of cellular proteins implicated in neurodegeneration, cancer, and infectious diseases. Protein SUMOylation is regulated by two opposing reactions: conjugation—which is carried out by a system of enzymes that activate SUMO and couple it to targets, and deconjugation—which is carried out by members of a specialized protease family called sentrin‐specific proteases (SENPs) (2). 
SUMO PATHWAY.  Modification of proteins by SUMO is a dynamic and reversible process. Covalent interaction between SUMO and its targets is achieved by the formation of an isopeptide bond between the C terminus of mature SUMO and the ε‐amino group of a lysine residue in the acceptor protein. SUMO conjugation involves three enzymatic steps (Fig. 1) and begins with the ATP‐dependent activation of the SUMO C‐terminus by heterodimeric SUMO‐activating enzyme E1 (SAE1/SAE2). In the second step, activated SUMO is transferred to the E2 conjugating enzyme Ubc9. Ubc9 can directly recognize substrate proteins, at least in vitro, and modifies a lysine residue that is sometimes within the short consensus sequence ΨKXE (Ψ is a large hydrophobic residue, K is a modified lysine, X is any amino acid, and E is a glutamic acid) present in many known SUMO substrates. Although in vitro SUMOylation can be fulfilled by E1 and E2 enzymes, E3‐like factors greatly enhance SUMOylation and may be important in regulating substrate selection in vivo (3, 4). Eventually, SUMO is removed intact from its substrate SUMOylated proteins, and so the SUMOylation/deSUMOylation cycle regulates SUMOs function (Fig. 1). Thus, depending on the cell regulation factors, SENPs can be involved in both the activation of SUMO precursors (endopeptidase cleavage) and deconjugation of the targets (isopeptidase cleavage) (5). A similar cycle takes place in the case of SENP8; however, this member of the SENP family acts on Nedd8 substrate rather than SUMO (6, 7).

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