Structural Snapshots of 26S Proteasome Reveal Tetraubiquitin-Induced Conformations

Molecular Cell
Zhanyu DingYao Cong

Abstract

The 26S proteasome is the ATP-dependent protease responsible for regulating the proteome of eukaryotic cells through degradation of mainly ubiquitin-tagged substrates. In order to understand how proteasome responds to ubiquitin signal, we resolved an ensemble of cryo-EM structures of proteasome in the presence of K48-Ub4, with three of them resolved at near-atomic resolution. We identified a conformation with stabilized ubiquitin receptors and a previously unreported orientation of the lid, assigned as a Ub-accepted state C1-b. We determined another structure C3-b with localized K48-Ub4 to the toroid region of Rpn1, assigned as a substrate-processing state. Our structures indicate that tetraUb induced conformational changes in proteasome could initiate substrate degradation. We also propose a CP gate-opening mechanism involving the propagation of the motion of the lid to the gate through the Rpn6-α2 interaction. Our results enabled us to put forward a model of a functional cycle for proteasomes induced by tetraUb and nucleotide.

Citations

Oct 31, 2019·Biological Chemistry·Parijat Majumder, Wolfgang Baumeister
Aug 25, 2019·Biomolecules·Bernat Coll-Martínez, Bernat Crosas
Jul 29, 2020·Journal of Cell Science·Annette Aichem, Marcus Groettrup
Feb 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Galen A Collins, Alfred L Goldberg
Dec 10, 2020·Polymers·Lucia Račková, Erika Csekes
Nov 20, 2020·The FEBS Journal·Xiang ChenKylie J Walters
Dec 16, 2020·Biochimica Et Biophysica Acta. Proteins and Proteomics·Eri SakataWolfgang Baumeister
Mar 18, 2021·Biochemical Society Transactions·Indrajit Sahu, Michael H Glickman
Jun 6, 2020·The Journal of Physical Chemistry. B·Arjun SahaArieh Warshel
Jun 24, 2021·Proceedings of the National Academy of Sciences of the United States of America·Julianna R CrestiDaniel A Kraut
Jul 10, 2021·Nature Chemical Biology·Yuanyuan YuMinglei Zhao
Dec 7, 2021·Proceedings of the National Academy of Sciences of the United States of America·Wei ZhengYao Cong

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