MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes.
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.
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Syed Arif
SA
Abdul Rehman
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Yosua Adi
YA
Kristariyanto
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Soo-Youn
SY
Choi
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Pedro Junior
PJ
Nkosi
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Simone
S
Weidlich
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
Karim
K
Labib
Institute for Genetics, University of Cologne, Zülpicher Straße 47a, 50674 Cologne, Germany.
Kay
K
Hofmann
MRC Protein Phosphorylation & Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK. Electronic address: ykulathu@dundee.ac.uk.
Yogesh
Y
Kulathu
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D000072017:Deubiquitinating Enzymes / Q000737:chemistry / Q000378:metabolism*; D019143:Evolution, Molecular; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism*; D017510:Protein Folding; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000737:chemistry / Q000378:metabolism; D054875:Ubiquitination
C568300:MINDY3 protein, human; D008565:Membrane Proteins; D009687:Nuclear Proteins; C000603301:TVP23B protein, human; D025521:Tumor Suppressor Proteins; D025821:Polyubiquitin; D000072017:Deubiquitinating Enzymes; C000622060:MINDY1 protein, human; C000612883:MINDY2 protein, human; D043222:Ubiquitin Thiolesterase