2. Academic Validation
  3. A family of unconventional deubiquitinases with modular chain specificity determinants

A family of unconventional deubiquitinases with modular chain specificity determinants

  • Nat Commun. 2018 Feb 23;9(1):799. doi: 10.1038/s41467-018-03148-5.
Thomas Hermanns 1,  Christian Pichlo 2,  Ilka Woiwode 1,  Karsten Klopffleisch 1,  Katharina F Witting 3,  Huib Ovaa 3,  Ulrich Baumann 2,  Kay Hofmann 4
Affiliations

Affiliations

  • 1 Institute for Genetics, University of Cologne, Zülpicher Str. 47a, 50674, Cologne, Germany.
  • 2 Institute of Biochemistry, University of Cologne, Zülpicher Str. 47, 50674, Cologne, Germany.
  • 3 Department of Chemical Immunology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC, Leiden, The Netherlands.
  • 4 Institute for Genetics, University of Cologne, Zülpicher Str. 47a, 50674, Cologne, Germany. [email protected].
PMID: 29476094 DOI: 10.1038/s41467-018-03148-5
Abstract

Deubiquitinating enzymes (DUBs) regulate ubiquitin signaling by trimming ubiquitin chains or removing ubiquitin from modified substrates. Similar activities exist for ubiquitin-related modifiers, although the enzymes involved are usually not related. Here, we report human ZUFSP (also known as ZUP1 and C6orf113) and fission yeast Mug105 as founding members of a DUB family different from the six known DUB classes. The crystal structure of human ZUFSP in covalent complex with propargylated ubiquitin shows that the DUB family shares a fold with UFM1- and Atg8-specific proteases, but uses a different active site more similar to canonical DUB enzymes. ZUFSP family members differ widely in linkage specificity through differential use of modular ubiquitin-binding domains (UBDs). While the minimalistic Mug105 prefers K48 chains, ZUFSP uses multiple UBDs for its K63-specific endo-DUB activity. K63 specificity, localization, and protein interaction network suggest a role for ZUFSP in DNA damage response.

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