Suramin Inhibits Cullin-RING E3 Ubiquitin Ligases

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2016 Mar 23

PMID 27001857

Citations 30

Authors

Kenneth Wu

Robert A Chong

Qing Yu

Jin Bai

Donald E Spratt

Kevin Ching

Chan Lee

Haibin Miao

Inger Tappin

Jerard Hurwitz

Ning Zheng

Gary S Shaw

Yi Sun

Dan P Felsenfeld

Roberto Sanchez

Jun-Nian Zheng

Zhen-Qiang Pan

Affiliations

Soon will be listed here.

Abstract

Cullin-RING E3 ubiquitin ligases (CRL) control a myriad of biological processes by directing numerous protein substrates for proteasomal degradation. Key to CRL activity is the recruitment of the E2 ubiquitin-conjugating enzyme Cdc34 through electrostatic interactions between E3's cullin conserved basic canyon and the acidic C terminus of the E2 enzyme. This report demonstrates that a small-molecule compound, suramin, can inhibit CRL activity by disrupting its ability to recruit Cdc34. Suramin, an antitrypansomal drug that also possesses antitumor activity, was identified here through a fluorescence-based high-throughput screen as an inhibitor of ubiquitination. Suramin was shown to target cullin 1's conserved basic canyon and to block its binding to Cdc34. Suramin inhibits the activity of a variety of CRL complexes containing cullin 2, 3, and 4A. When introduced into cells, suramin induced accumulation of CRL substrates. These observations help develop a strategy of regulating ubiquitination by targeting an E2-E3 interface through small-molecule modulators.

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