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Control and enzymatic activation of the APC/C ubiquitin ligase system (360G-Wellcome-205150_Z_16_Z)

<p>CDK1 and APC/C are two key regulatory enzymes controlling the cell division, growth, differentiation and death, through phosphorylation and ubiquitylation, respectively. Although it has long been apparent that phosphorylation modifies APC/C function, the challenges posed by the need for functional assays to study this control puts the elucidation of the molecular basis of phosphorylation control beyond our grasp. We have recently overcome these limitations with a pipeline that uses reconstituted recombinant APC/C in <em>Xenopus</em> cell free extracts to show how CDK1 activates the APC/C through coordinated phosphorylation of Apc3 and Apc1. We will now extend this pipeline with targeted assays that will determine how phosphatases regulate these phosphorylation events. Because we have found that the disordered loop domains of APC/C subunits are targets for both post-translational modifications (PTMs) and interacting partners, including protein phosphatases, we will study how the loop domain controls the APC/C. Cell cycle specific and stress-dependent PTMs and binding proteins will be identified and we will determine their impact upon APC/C-dependent ubiquitylation. This approach of combining high throughput reconstitution mutated apo-APC/C in extracts from which any component of interest can be depleted offers a unique opportunity to gain an unprecedented insight into APC/C function and control.&nbsp;</p>

£1,547,248

30 Nov 2016

Grant details
Amount Awarded 1547248
Applicant Surname Yamano
Approval Committee Science Interview Panel
Award Date 2016-11-30T00:00:00+00:00
Financial Year 2016/17
Grant Programme: Title Investigator Award in Science
Internal ID 205150/Z/16/Z
Lead Applicant Dr Hiro Yamano
Planned Dates: End Date 2022-09-04T00:00:00+00:00
Planned Dates: Start Date 2017-09-04T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Greater London
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