Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity

Kumar, A., Chaugule, V. K. , Condos, T. E.C., Barber, K. R., Johnson, C., Toth, R., Sundaramoorthy, R., Knebel, A., Shaw, G. S. and Walden, H. (2017) Parkin–phosphoubiquitin complex reveals cryptic ubiquitin-binding site required for RBR ligase activity. Nature Structural and Molecular Biology, 24(5), pp. 475-483. (doi: 10.1038/nsmb.3400) (PMID:28414322) (PMCID:PMC5420311)

Abstract

RING-between-RING (RBR) E3 ligases are a class of ubiquitin ligases distinct from RING or HECT E3 ligases. An important RBR ligase is Parkin, mutations in which lead to early-onset hereditary Parkinsonism. Parkin and other RBR ligases share a catalytic RBR module but are usually autoinhibited and activated via distinct mechanisms. Recent insights into Parkin regulation predict large, unknown conformational changes during Parkin activation. However, current data on active RBR ligases reflect the absence of regulatory domains. Therefore, it remains unclear how individual RBR ligases are activated, and whether they share a common mechanism. We now report the crystal structure of a human Parkin–phosphoubiquitin complex, which shows that phosphoubiquitin binding induces movement in the 'in-between RING' (IBR) domain to reveal a cryptic ubiquitin-binding site. Mutation of this site negatively affects Parkin's activity. Furthermore, ubiquitin binding promotes cooperation between Parkin molecules, which suggests a role for interdomain association in the RBR ligase mechanism.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK (grant 17739 to H.W.), the Medical Research Council (grant MC_UU_12016/12 to H.W.), the EMBO Young Investigator Programme (to H.W.), the Canadian Institutes of Health Research (grant MOP-14606 to G.S.S.), and the Canada Research Chairs Program (G.S.S.).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Chaugule, Dr Viduth and Walden, Professor Helen
• Authors: Kumar, A., Chaugule, V. K., Condos, T. E.C., Barber, K. R., Johnson, C., Toth, R., Sundaramoorthy, R., Knebel, A., Shaw, G. S., and Walden, H.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Nature Structural and Molecular Biology
• Publisher: Nature Publishing Group
• ISSN: 1545-9993
• ISSN (Online): 1545-9985
• Published Online: 17 April 2017
• Copyright Holders: Copyright © 2017 Macmillan Publishers Limited, part of Springer Nature
• First Published: First published in Nature Structural and Molecular Biology 24(5):475-783
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.