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.
Copyright (c) 2008 IUBMB
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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