Structural Basis for Substrate Recognition and Chemical Inhibition of Oncogenic MAGE Ubiquitin Ligases

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Oct 2

PMID 33004795

Citations 12

Authors

Seung Wook Yang

Xin Huang

Wenwei Lin

Jaeki Min

Darcie J Miller

Anand Mayasundari

Patrick Rodrigues

Elizabeth C Griffith

Clifford T Gee

Lei Li

Wei Li

Richard E Lee

Zoran Rankovic

Taosheng Chen

Patrick Ryan Potts

Affiliations

Soon will be listed here.

Abstract

Testis-restricted melanoma antigen (MAGE) proteins are frequently hijacked in cancer and play a critical role in tumorigenesis. MAGEs assemble with E3 ubiquitin ligases and function as substrate adaptors that direct the ubiquitination of novel targets, including key tumor suppressors. However, how MAGEs recognize their targets is unknown and has impeded the development of MAGE-directed therapeutics. Here, we report the structural basis for substrate recognition by MAGE ubiquitin ligases. Biochemical analysis of the degron motif recognized by MAGE-A11 and the crystal structure of MAGE-A11 bound to the PCF11 substrate uncovered a conserved substrate binding cleft (SBC) in MAGEs. Mutation of the SBC disrupted substrate recognition by MAGEs and blocked MAGE-A11 oncogenic activity. A chemical screen for inhibitors of MAGE-A11:substrate interaction identified 4-Aminoquinolines as potent inhibitors of MAGE-A11 that show selective cytotoxicity. These findings provide important insights into the large family of MAGE ubiquitin ligases and identify approaches for developing cancer-specific therapeutics.

Citing Articles

Structural basis for RAD18 regulation by MAGEA4 and its implications for RING ubiquitin ligase binding by MAGE family proteins.

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Proteomic Analysis Revealed the Potential Role of MAGE-D2 in the Therapeutic Targeting of Triple-Negative Breast Cancer.

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The Melanoma-Associated Antigen Family A (MAGE-A): A Promising Target for Cancer Immunotherapy?.

Alsalloum A, Shevchenko J, Sennikov S Cancers (Basel). 2023; 15(6).

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