8DWS

Full-length E47K SPOP

Summary for 8DWS

• Entry DOI: 10.2210/pdb8dws/pdb
• EMDB information: 27758
• Descriptor: Speckle-type POZ protein (1 entity in total)
• Functional Keywords: spop, ubiquitination, cullin, oncoprotein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 7
• Total formula weight: 295283.95

Authors

Cuneo, M.J.,Mittag, T.,O'Flynn, B.,Lo, Y.H. (deposition date: 2022-08-02, release date: 2023-01-18, Last modification date: 2024-11-20)

Primary citation

Cuneo, M.J.,O'Flynn, B.G.,Lo, Y.H.,Sabri, N.,Mittag, T.
Higher-order SPOP assembly reveals a basis for cancer mutant dysregulation.
Mol.Cell, 83:731-745.e4, 2023

PubMed Abstract: 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.

PubMed: 36693379
DOI: 10.1016/j.molcel.2022.12.033

Experimental method

ELECTRON MICROSCOPY (3.73 Å)