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

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. Pros-tate 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 incon-spicuous 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.

Automated summary

The speckle-type POZ protein (SPOP) functions as a receptor in the Cullin3-RING ubiquitin ligase (CRL3) to recognize substrates involved in cell growth, survival, and signaling. SPOP mutations have been linked to the development of various cancers, including prostate and endometrial cancers. While prostate cancer mutations affect the substrate-binding site, most endometrial cancer mutations are located in inconspicuous regions of SPOP, with unclear cancer-causing mechanisms. This study presents the structure of SPOP in its oligomeric form, revealing new interfaces crucial for its self-assembly and normal function, offering insights into the dysregulation of SPOP function due to cancer mutations.