Allosteric Regulation of Deubiquitylase Activity Through Ubiquitination

Overview

Journal Front Mol Biosci

Specialty Biology

Date 2015 May 20

PMID 25988170

Citations 8

Authors

Serena Faggiano

Rajesh P Menon

Geoff P Kelly

Sokol V Todi

K Matthew Scaglione

Petr V Konarev

Dmitri I Svergun

Henry L Paulson

Annalisa Pastore

Affiliations

Soon will be listed here.

Abstract

Ataxin-3, the protein responsible for spinocerebellar ataxia type-3, is a cysteine protease that specifically cleaves poly-ubiquitin chains and participates in the ubiquitin proteasome pathway. The enzymatic activity resides in the N-terminal Josephin domain. An unusual feature of ataxin-3 is its low enzymatic activity especially for mono-ubiquitinated substrates and short ubiquitin chains. However, specific ubiquitination at lysine 117 in the Josephin domain activates ataxin-3 through an unknown mechanism. Here, we investigate the effects of K117 ubiquitination on the structure and enzymatic activity of the protein. We show that covalently linked ubiquitin rests on the Josephin domain, forming a compact globular moiety and occupying a ubiquitin binding site previously thought to be essential for substrate recognition. In doing so, ubiquitination enhances enzymatic activity by locking the enzyme in an activated state. Our results indicate that ubiquitin functions both as a substrate and as an allosteric regulatory factor. We provide a novel example in which a conformational switch controls the activity of an enzyme that mediates deubiquitination.

Citing Articles

ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3.

Hernandez-Carralero E, Quinet G, Freire R Expert Rev Mol Med. 2024; 26:e19.

PMID: 39320846 PMC: 11440613. DOI: 10.1017/erm.2024.10.

Friend or foe? Reciprocal regulation between E3 ubiquitin ligases and deubiquitinases.

Bolhuis D, Emanuele M, Brown N Biochem Soc Trans. 2024; 52(1):241-267.

PMID: 38414432 PMC: 11349938. DOI: 10.1042/BST20230454.

Lysine 117 on ataxin-3 modulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3.

Blount J, Patel N, Libohova K, Harris A, Tsou W, Sujkowski A J Neurol Sci. 2023; 454:120828.

PMID: 37865002 PMC: 10841544. DOI: 10.1016/j.jns.2023.120828.

Characterization of PMI-5011 on the Regulation of Deubiquitinating Enzyme Activity in Multiple Myeloma Cell Extracts.

Vaithiyanathan M, Yu Y, Rahnama A, Pettigrew J, Safa N, Liu D Biochem Eng J. 2021; 166.

PMID: 33716550 PMC: 7949241. DOI: 10.1016/j.bej.2020.107834.

Structural insights into the activity and regulation of human Josephin-2.

Grasty K, Weeks S, Loll P J Struct Biol X. 2020; 3:100011.

PMID: 32647816 PMC: 7337049. DOI: 10.1016/j.yjsbx.2019.100011.

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