MINDY-1 Is a Member of an Evolutionarily Conserved and Structurally Distinct New Family of Deubiquitinating Enzymes
| Autor: | Syed Arif, Abdul Rehman, Yosua Adi, Kristariyanto, Soo-Youn, Choi, Pedro Junior, Nkosi, Simone, Weidlich, Karim, Labib, Kay, Hofmann, Yogesh, Kulathu |
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| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular Protein Folding Deubiquitinating Enzymes Tumor Suppressor Proteins Ubiquitination Membrane Proteins Nuclear Proteins Eukaryota Cell Biology Substrate Specificity Evolution Molecular Structure-Activity Relationship Short Article Catalytic Domain Humans Amino Acid Sequence Polyubiquitin Ubiquitin Thiolesterase Molecular Biology Conserved Sequence |
| Zdroj: | Molecular Cell |
| ISSN: | 1097-2765 |
| DOI: | 10.1016/j.molcel.2016.05.009 |
| Popis: | Summary 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. Graphical Abstract Highlights • MINDY is a new family of DUBs consisting of FAM63A, FAM63B, FAM188A, and FAM188B • MINDY DUBs are highly selective at cleaving K48-linked polyubiquitin • Catalytic domain of MINDY-1 adopts a distinct fold with no homology to any known DUB • Human MINDY-1 trims ubiquitin chains from the distal end Abdul Rehman et al. discover a new family of deubiquitinating enzymes called MINDY. This structurally distinct family of DUBs is highly selective at cleaving K48-linked polyubiquitin chains. |
| Databáze: | OpenAIRE |
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