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Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2

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 e...

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Autores principales: Abdul Rehman, Syed Arif, Armstrong, Lee A., Lange, Sven M., Kristariyanto, Yosua Adi, Gräwert, Tobias W., Knebel, Axel, Svergun, Dmitri I., Kulathu, Yogesh
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550791/
https://www.ncbi.nlm.nih.gov/pubmed/34529927
http://dx.doi.org/10.1016/j.molcel.2021.08.024
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author Abdul Rehman, Syed Arif
Armstrong, Lee A.
Lange, Sven M.
Kristariyanto, Yosua Adi
Gräwert, Tobias W.
Knebel, Axel
Svergun, Dmitri I.
Kulathu, Yogesh
author_facet Abdul Rehman, Syed Arif
Armstrong, Lee A.
Lange, Sven M.
Kristariyanto, Yosua Adi
Gräwert, Tobias W.
Knebel, Axel
Svergun, Dmitri I.
Kulathu, Yogesh
author_sort Abdul Rehman, Syed Arif
collection PubMed
description 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.
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spelling pubmed-85507912021-10-29 Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2 Abdul Rehman, Syed Arif Armstrong, Lee A. Lange, Sven M. Kristariyanto, Yosua Adi Gräwert, Tobias W. Knebel, Axel Svergun, Dmitri I. Kulathu, Yogesh Mol Cell Article 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. Cell Press 2021-10-21 /pmc/articles/PMC8550791/ /pubmed/34529927 http://dx.doi.org/10.1016/j.molcel.2021.08.024 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Abdul Rehman, Syed Arif
Armstrong, Lee A.
Lange, Sven M.
Kristariyanto, Yosua Adi
Gräwert, Tobias W.
Knebel, Axel
Svergun, Dmitri I.
Kulathu, Yogesh
Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title_full Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title_fullStr Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title_full_unstemmed Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title_short Mechanism of activation and regulation of deubiquitinase activity in MINDY1 and MINDY2
title_sort mechanism of activation and regulation of deubiquitinase activity in mindy1 and mindy2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8550791/
https://www.ncbi.nlm.nih.gov/pubmed/34529927
http://dx.doi.org/10.1016/j.molcel.2021.08.024
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