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. Epub 2016 Jun 9.


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.

MeSH terms

  • Amino Acid Sequence
  • Catalytic Domain
  • Conserved Sequence
  • Deubiquitinating Enzymes / chemistry
  • Deubiquitinating Enzymes / metabolism*
  • Evolution, Molecular*
  • Humans
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Polyubiquitin / metabolism*
  • Protein Folding
  • Structure-Activity Relationship
  • Substrate Specificity
  • Tumor Suppressor Proteins / chemistry
  • Tumor Suppressor Proteins / metabolism
  • Ubiquitin Thiolesterase / chemistry
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitination


  • MINDY3 protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • TVP23B protein, human
  • Tumor Suppressor Proteins
  • Polyubiquitin
  • Deubiquitinating Enzymes
  • MINDY1 protein, human
  • MINDY2 protein, human
  • Ubiquitin Thiolesterase