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

DOI: 10.1016/j.molcel.2021.08.024 DOI Help

Authors: Syed Arif Abdul Rehman (University of Dundee) , Lee A. Armstrong (University of Dundee) , Sven M. Lange (University of Dundee) , Yosua Adi Kristariyanto (University of Dundee) , Tobias W. Gräwert (European Molecular Biology Laboratory) , Axel Knebel (University of Dundee) , Dmitri I. Svergun (European Molecular Biology Laboratory) , Yogesh Kulathu (University of Dundee)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Molecular Cell , VOL 63

State: Published (Approved)
Published: September 2021

Open Access Open Access

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.

Journal Keywords: ubiquitylation; deubiquitinase; crystal structure; polyubiquitin; protease; enzyme mechanism; protein degradationl proteasome; conformational change; autoinhibition

Diamond Keywords: Enzymes

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I03-Macromolecular Crystallography

Other Facilities: ID23-1, ID23-2, ID-29, ID30-A1, and ID30B at ESRF; P12 at PETRA III

Added On: 18/10/2021 13:54

Documents:
1-s2.0-S1097276521006912-main.pdf

Discipline Tags:

Biochemistry Catalysis Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)