Design Principles of a Universal Protein Degradation Machine

Overview

Journal J Mol Biol

Publisher Elsevier

Specialties Microbiology
Molecular Biology

Date 2012 Nov 14

PMID 23147216

Citations 35

Authors

Mary E Matyskiela

Andreas Martin

Affiliations

Soon will be listed here.

Abstract

The 26S proteasome is a 2.5-MDa, 32-subunit ATP-dependent protease that is responsible for the degradation of ubiquitinated protein targets in all eukaryotic cells. This proteolytic machine consists of a barrel-shaped peptidase capped by a large regulatory particle, which contains a heterohexameric AAA+ unfoldase as well as several structural modules of previously unknown function. Recent electron microscopy (EM) studies have allowed major breakthroughs in understanding the architecture of the regulatory particle, revealing that the additional modules provide a structural framework to position critical, ubiquitin-interacting subunits and thus allow the 26S proteasome to function as a universal degradation machine for a wide variety of protein substrates. The EM studies have also uncovered surprising asymmetries in the spatial arrangement of proteasome subunits, yet the functional significance of these architectural features remains unclear. This review will summarize the recent findings on 26S proteasome structure and discuss the mechanistic implications for substrate binding, deubiquitination, unfolding, and degradation.

Citing Articles

Structural landscape of AAA+ ATPase motor states in the substrate-degrading human 26S proteasome reveals conformation-specific binding of TXNL1.

Arkinson C, Gee C, Zhang Z, Dong K, Martin A bioRxiv. 2024; .

PMID: 39574680 PMC: 11580985. DOI: 10.1101/2024.11.08.622731.

Structural insights into the Clp protein degradation machinery.

Xu X, Wang Y, Huang W, Li D, Deng Z, Long F mBio. 2024; 15(4):e0003124.

PMID: 38501868 PMC: 11005422. DOI: 10.1128/mbio.00031-24.

Ubiquitin modulates 26 proteasome conformational dynamics and promotes substrate degradation.

Jonsson E, Htet Z, Bard J, Dong K, Martin A Sci Adv. 2022; 8(51):eadd9520.

PMID: 36563145 PMC: 9788759. DOI: 10.1126/sciadv.add9520.

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease.

Wang L, Sun X, He J, Liu Z Front Cell Dev Biol. 2021; 9:706997.

PMID: 34513839 PMC: 8424196. DOI: 10.3389/fcell.2021.706997.

Cooperative Binding of the Cationic Porphyrin Tris-T4 Enhances Catalytic Activity of 20S Proteasome Unveiling a Complex Distribution of Functional States.

Santoro A, DUrso A, Cunsolo A, Milardi D, Purrello R, Sbardella D Int J Mol Sci. 2020; 21(19).

PMID: 33003385 PMC: 7582714. DOI: 10.3390/ijms21197190.

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