PROSITE documentation PDOC00750
Ubiquitin specific protease (USP) domain signatures and profile


Protein ubiquitination is a reversible posttranslational modification, which affects a large number of cellular processes including protein degradation, trafficking, cell signaling and the DNA damage response. Ubiquitination is reversible, and dedicated deubiquitinases exist which hydrolyze isopeptide bonds. Ubiquitin specific proteases (USPs) (EC are the largest family of deubiquitinating enzymes. USP domains consist of a common conserved catalytic core which is interspersed at five points with insertions, some of which as large as the catalytic domain itself. The insertions can fold into independent domains that can be involved in the regulation of deubiquitinase activity. As commonly found in signaling proteins, many USP deubiquitinases have a modular architecture, and not only contain a catalytic domain but also additional protein-protein interaction and localization domains. Most USP domains cleave the isopeptide linkage between two ubiquitin molecules, and hence contain (at least) two ubiquitin-binding sites, one for the distal ubiquitin, the C-terminus of which is linked to the Lys residue on the proximal ubiquitin in a second, proximal binding site [1]. The USP domain forms the peptidase family C19 [2,E1].

The USP catalytic core can be divided into six conserved boxes that are present in all USP domains. Box 1 contains the catalytic Cys residue, box 5 contains the catalytic His, and box 6 contains the catalytic Asp/Asn residue. All boxes show several additional conserved features and residues. Boxes 3 and 4 contain a Cys-X-X-Cys motif each, which have been shown to constitute a functional zinc-binding motif. Potentially, zinc-binding facilitates folding of the USP core, helping the interaction of sequence motifs some few hundred residues apart. USP domains share a common conserved fold (see <PDB:1NBF>). The USP domain resembles an open hand containing Thumb, Palm and Fingers subdomains. The catalytic triad resides between the Thumb (Cys) and Palm subdomains (His/Asp) [1].

Some proteins kwown to contain an USP domain are listed below:

  • Yeast UBP1, UBP2, UBP3, UBP4 (or DOA4/SSV7), UBP5, UBP7, UBP9, UBP10, UBP11, UBP12, UBP13, UBP14, UBP15 and UBP16.
  • Human tre-2.
  • Human isopeptidase T.
  • Human isopeptidase T-3.
  • Mammalian Ode-1.
  • Mammalian Unp.
  • Mouse Dub-1.
  • Drosophila fat facets protein (gene faf).
  • Mammalian faf homolog.
  • Drosophila D-Ubp-64E.
  • Caenorhabditis elegans hypothetical protein R10E11.3.
  • Caenorhabditis elegans hypothetical protein K02C4.3.

We have developed two signature patterns for the USP domain. The first one around the catalytic cysteine in box 1 and the second around the catalytic histidine in box 5. We also developed a profile which covers the entire USP domain.

Last update:

December 2013 / Profile and text revised.


Technical section

PROSITE methods (with tools and information) covered by this documentation:

USP_3, PS50235; Ubiquitin specific protease (USP) domain profile  (MATRIX)

USP_1, PS00972; Ubiquitin specific protease (USP) domain signature 1  (PATTERN)

USP_2, PS00973; Ubiquitin specific protease (USP) domain signature 2  (PATTERN)


1AuthorsYe Y. Scheel H. Hofmann K. Komander D.
TitleDissection of USP catalytic domains reveals five common insertion points.
SourceMol. Biosyst. 5:1797-1808(2009).
PubMed ID19734957

2AuthorsRawlings N.D. Barrett A.J.
TitleFamilies of cysteine peptidases.
SourceMethods Enzymol. 244:461-486(1994).
PubMed ID7845226


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