Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation.

Autor:	Cuneo MJ; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA., O'Flynn BG; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA., Lo YH; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA., Sabri N; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA., Mittag T; Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA. Electronic address: tanja.mittag@stjude.org.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2023 Mar 02; Vol. 83 (5), pp. 731-745.e4. Date of Electronic Publication: 2023 Jan 23.
DOI:	10.1016/j.molcel.2022.12.033
Abstrakt:	The speckle-type POZ protein (SPOP) functions in the Cullin3-RING ubiquitin ligase (CRL3) as a receptor for the recognition of substrates involved in cell growth, survival, and signaling. SPOP mutations have been attributed to the development of many types of cancers, including prostate and endometrial cancers. Prostate cancer mutations localize in the substrate-binding site of the substrate recognition (MATH) domain and reduce or prevent binding. However, most endometrial cancer mutations are dispersed in seemingly inconspicuous solvent-exposed regions of SPOP, offering no clear basis for their cancer-causing and peculiar gain-of-function properties. Herein, we present the first structure of SPOP in its oligomeric form, uncovering several new interfaces important for SPOP self-assembly and normal function. Given that many previously unaccounted-for cancer mutations are localized in these newly identified interfaces, we uncover molecular mechanisms underlying dysregulation of SPOP function, with effects ranging from gross structural changes to enhanced self-association, and heightened stability and activity. Competing Interests: Declaration of interests T.M. was a consultant for Faze Medicines, Inc. and is a member of the journal’s advisory board. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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