2. Academic Validation
  3. MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes

MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes

  • Mol Cell. 2016 Jul 7;63(1):146-55. doi: 10.1016/j.molcel.2016.05.009.
Syed Arif Abdul Rehman 1,  Yosua Adi Kristariyanto 1,  Soo-Youn Choi 1,  Pedro Junior Nkosi 1,  Simone Weidlich 1,  Karim Labib 1,  Kay Hofmann 2,  Yogesh Kulathu 3
Affiliations

Affiliations

  • 1 MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
  • 2 Institute for Genetics, University of Cologne, Zülpicher Straße 47a, 50674 Cologne, Germany.
  • 3 MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: [email protected].
PMID: 27292798 DOI: 10.1016/j.molcel.2016.05.009
Abstract

Deubiquitinating enzymes (DUBs) remove ubiquitin (Ub) from Ub-conjugated substrates to regulate the functional outcome of ubiquitylation. Here we report the discovery of a new family of DUBs, which we have named MINDY (motif interacting with Ub-containing novel DUB family). Found in all eukaryotes, MINDY-family DUBs are highly selective at cleaving K48-linked polyUb, a signal that targets proteins for degradation. We identify the catalytic activity to be encoded within a previously unannotated domain, the crystal structure of which reveals a distinct protein fold with no homology to any of the known DUBs. The crystal structure of MINDY-1 (also known as FAM63A) in complex with propargylated Ub reveals conformational changes that realign the active site for catalysis. MINDY-1 prefers cleaving long polyUb chains and works by trimming chains from the distal end. Collectively, our results reveal a new family of DUBs that may have specialized roles in regulating proteostasis.

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