PXD037287 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif drives c-Src disfunction in cancer |
Description | The allosteric mechanisms that control the different functional and conformational states of oncogenic kinases, and how these molecular switches can be targeted and therapeutically exploited remains largely unexplored. Here we show that c-terminal Tyr 530 is a de facto c- Src auto-phosphorylation site with slow time-resolution kinetics and strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes fast kinetics and a cis-to-trans phosphorylation-switch that controls c-terminal Tyr 530 phosphorylation, enzyme specificity and strikingly, c-Src non-catalytic function as a substrate. In line with this, we visualize by X-ray crystallography a snapshot of c-terminal Tyr 530 intermolecular phosphorylation between the enzyme and susbtrate acting kinases, and identify a functionally relevant c-terminal palindromic phospho-motif flanking Tyr 530 making important contacts at the interface. Perturbation of this phospho-motif accounts for c-Src disfunction in cancer, as indicated by viral and a colorectal cancer (CRC) associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 auto-phosphorylation and overall phospho-tyrosine activity. However, c-terminal truncated forms display a minor delay in the capacity to phosphorylate intact c-Src substrates surrogates. On the contrary, when these c-terminal variants were used as intact substrate surrogates themselves, they were equally and efficiently phosphorylated, but strikingly they resulted in the allosteric inhibition of the active kinase. Our work reveals a bi-directional crosstalk between activation and c-terminal segments driven by auto-phosphorylation that controls the allosteric interplay between enzyme and susbtrate acting kinases. These findings have important implications for the drug-design and development of next generation c-Src inhibitors targeting non-catalytic and/or allosteric vulnerabilities. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_06:02:29.624.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Eduardo Zarzuela |
SpeciesList | scientific name: Escherichia coli; NCBI TaxID: 562; |
ModificationList | acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Q Exactive |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-10-11 03:55:58 | ID requested | |
1 | 2023-09-04 02:20:22 | announced | |
⏵ 2 | 2024-10-22 06:02:30 | announced | 2024-10-22: Updated project metadata. |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Src, phosphorylation |
Contact List
Javier Muñoz Peralta |
contact affiliation | CNIO |
contact email | javier.munozperalta@osakidetza.eus |
lab head | |
Eduardo Zarzuela |
contact affiliation | Centro Nacional de Investigaciones Oncológicas |
contact email | eduzarfer@gmail.com |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD037287
- Label: PRIDE project
- Name: An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif drives c-Src disfunction in cancer