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-Structure paper
タイトル | Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation. |
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ジャーナル・号・ページ | Mol Cell, Vol. 83, Issue 5, Page 731-745.e4, Year 2023 |
掲載日 | 2023年3月2日 |
著者 | Matthew J Cuneo / Brian G O'Flynn / Yu-Hua Lo / Nafiseh Sabri / Tanja Mittag / |
PubMed 要旨 | 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 ...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. |
リンク | Mol Cell / PubMed:36693379 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 3.4 - 6.2 Å |
構造データ | EMDB-27758, PDB-8dws: EMDB-27759: SPOP W22R Tetrameric Form EMDB-27760: SPOP W22R Hexameric form EMDB-27761, PDB-8dwv: |
化合物 | ChemComp-HOH: |
由来 |
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キーワード | ONCOPROTEIN / SPOP / ubiquitination / cullin |