Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38103, USA.
Mol Cell. 2023 Mar 2;83(5):731-745.e4. doi: 10.1016/j.molcel.2022.12.033. Epub 2023 Jan 23.
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.
斑点型 POZ 蛋白 (SPOP) 在 Cullin3-RING 泛素连接酶 (CRL3) 中作为识别参与细胞生长、存活和信号转导的底物的受体发挥作用。SPOP 突变与许多类型的癌症的发展有关，包括前列腺癌和子宫内膜癌。前列腺癌突变定位于底物识别（MATH）结构域的底物结合位点，并减少或阻止结合。然而，大多数子宫内膜癌突变分散在 SPOP 中看似不起眼的溶剂暴露区域，没有明确的基础来解释它们的致癌和特殊的功能获得性质。在此，我们首次展示了 SPOP 的寡聚形式结构，揭示了几个对 SPOP 自组装和正常功能很重要的新界面。鉴于许多以前未被解释的癌症突变定位于这些新鉴定的界面中，我们揭示了 SPOP 功能失调的分子机制，其影响范围从明显的结构变化到增强的自组装，以及更高的稳定性和活性。
