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Self-assembly Drives the Control of the SPOP Cullin–Ring Ligase

The covalent modification of proteins with a suite of molecular tags, a process termed post-translational modification, is a powerful means to enhance the proteomic complexity of an organism far beyond that which is directly encoded by its genome. A particularly widespread form of modification involves the conjugation of the protein ubiquitin to specified substrates, which serves to regulate numerous cellular processes. The mechanism of ubiquitin conjugation, known as ubiquitylation, requires E3 ubiquitin ligases that specify and recruit substrate proteins for ubiquitin conjugation. Recent insights into the mechanisms of ubiquitylation demonstrate that E3 ligases can possess active regulatory properties beyond those of a simple assembly scaffold.
This thesis describes the dimeric structure of the E3 ligase adaptor protein SPOP in complex with the N-terminal domain of Cul3 at 2.4 Å resolution. Here, it is demonstrated that SPOP forms large oligomers that can form heteromeric species with the closely related paralog SPOPL. In combination, SPOP and SPOPL form a molecular rheostat that can fine-tune E3 ubiquitin ligase activity by affecting the oligomeric state of the E3 complex. These results reveal a mechanism through which adaptor protein self-assembly may provide a graded level of regulation of the SPOP/Cul3 E3 ligase toward its multiple protein substrates.

Identiferoai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/43546
Date09 January 2014
CreatorsErrington, Wesley James
ContributorsPrivé, Gilbert G.
Source SetsUniversity of Toronto
Languageen_ca
Detected LanguageEnglish
TypeThesis

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