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

Cuneo, Matthew J.; O’Flynn, Brian G.; Lo, Yu-Hua; Sabri, Nafiseh; Mittag, Tanja

doi:10.1016/j.molcel.2022.12.033

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

Journal Article · Mon Jan 23 00:00:00 EST 2023 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2022.12.033· OSTI ID:2425479

^[1]; O’Flynn, Brian G. ^[1]; Lo, Yu-Hua ^[2]; Sabri, Nafiseh ^[1]; ^[1]

St. Jude Children’s Research Hospital, Memphis, TN (United States)
St. Jude Children’s Research Hospital, Memphis, TN (United States); Eli Lilly & Company, San Diego, CA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Brookhaven National Laboratory (BNL), Upton, NY (United States). National Synchrotron Light Source II (NSLS-II)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: SC0012704

OSTI ID:: 2425479

Journal Information:: Molecular Cell, Journal Name: Molecular Cell Journal Issue: 5 Vol. 83; ISSN 1097-2765

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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