Allosteric mechanism for site-specific ubiquitination of FANCD2

Chaugule, V. K., Arkinson, C., Rennie, M. L. , Kämäräinen, O., Toth, R. and Walden, H. (2020) Allosteric mechanism for site-specific ubiquitination of FANCD2. Nature Chemical Biology, 16, pp. 291-301. (doi: 10.1038/s41589-019-0426-z) (PMID:31873223)

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Abstract

DNA-damage repair is implemented by proteins that are coordinated by specialized molecular signals. One such signal in the Fanconi anemia (FA) pathway for the repair of DNA interstrand crosslinks is the site-specific monoubiquitination of FANCD2 and FANCI. The signal is mediated by a multiprotein FA core complex (FA-CC) however, the mechanics for precise ubiquitination remain elusive. We show that FANCL, the RING-bearing module in FA-CC, allosterically activates its cognate ubiqutin-conjugating enzyme E2 UBE2T to drive site-specific FANCD2 ubiquitination. Unlike typical RING E3 ligases, FANCL catalyzes ubiquitination by rewiring the intraresidue network of UBE2T to influence the active site. Consequently, a basic triad unique to UBE2T engages a structured acidic patch near the target lysine on FANCD2. This three-dimensional complementarity, between the E2 active site and substrate surface, induced by FANCL is central to site-specific monoubiquitination in the FA pathway. Furthermore, the allosteric network of UBE2T can be engineered to enhance FANCL-catalyzed FANCD2–FANCI di-monoubiquitination without compromising site specificity.

Item Type:Articles
Additional Information:This work was supported by the Medical Research Council (grant number MC_UU_12016/12), the EMBO Young Investigator Programme (to H.W.) and the European Research Council (ERC-2015-CoG-681582 ICLUb consolidator grant to H.W.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Chaugule, Dr Viduth and Rennie, Dr Martin and Arkinson, Connor and Walden, Professor Helen and Kamarainen, Dr Outi
Authors: Chaugule, V. K., Arkinson, C., Rennie, M. L., Kämäräinen, O., Toth, R., and Walden, H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Nature Chemical Biology
Publisher:Nature Research
ISSN:1552-4450
ISSN (Online):1552-4469
Published Online:23 December 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Nature Chemical Biology 16:291-301
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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