6YJG

Crystal structure of MINDY1 mutant-Y114F

Summary for 6YJG

• Entry DOI: 10.2210/pdb6yjg/pdb
• Descriptor: Ubiquitin carboxyl-terminal hydrolase MINDY1 (1 entity in total)
• Functional Keywords: hydrolase, cysteine protease, isopeptidase and ubiquitin binding
• Biological source: Homo sapiens
• Total number of polymer chains: 1
• Total formula weight: 32022.22

Authors

Abdul Rehman, S.A.,Kulathu, Y. (deposition date: 2020-04-03, release date: 2021-04-14, Last modification date: 2024-01-24)

Primary citation

Abdul Rehman, S.A.,Armstrong, L.A.,Lange, S.M.,Kristariyanto, Y.A.,Grawert, T.W.,Knebel, A.,Svergun, D.I.,Kulathu, Y.
Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2.
Mol.Cell, 81:4176-4190.e6, 2021

PubMed Abstract: Of the eight distinct polyubiquitin (polyUb) linkages that can be assembled, the roles of K48-linked polyUb (K48-polyUb) are the most established, with K48-polyUb modified proteins being targeted for degradation. MINDY1 and MINDY2 are members of the MINDY family of deubiquitinases (DUBs) that have exquisite specificity for cleaving K48-polyUb, yet we have a poor understanding of their catalytic mechanism. Here, we analyze the crystal structures of MINDY1 and MINDY2 alone and in complex with monoUb, di-, and penta-K48-polyUb, identifying 5 distinct Ub binding sites in the catalytic domain that explain how these DUBs sense both Ub chain length and linkage type to cleave K48-polyUb chains. The activity of MINDY1/2 is inhibited by the Cys-loop, and we find that substrate interaction relieves autoinhibition to activate these DUBs. We also find that MINDY1/2 use a non-canonical catalytic triad composed of Cys-His-Thr. Our findings highlight multiple layers of regulation modulating DUB activity in MINDY1 and MINDY2.

PubMed: 34529927
DOI: 10.1016/j.molcel.2021.08.024

Experimental method

X-RAY DIFFRACTION (3.28 Å)