An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function

Hipólito Nicolás Cuesta-Hernández, Julia Contreras, Pablo Soriano-Maldonado, Jana Sánchez-Wandelmer, Wayland Yeung, Ana Martín-Hurtado, Inés G. Muñoz, Natarajan Kannan, Marta Llimargas, Javier Muñoz and Iván Plaza-Menacho ()
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Hipólito Nicolás Cuesta-Hernández: Spanish National Cancer Research Center (CNIO)
Julia Contreras: Spanish National Cancer Research Center (CNIO)
Pablo Soriano-Maldonado: Spanish National Cancer Research Center (CNIO)
Jana Sánchez-Wandelmer: Spanish National Cancer Research Center (CNIO)
Wayland Yeung: University of Georgia
Ana Martín-Hurtado: Spanish National Cancer Research Center (CNIO)
Inés G. Muñoz: Spanish National Cancer Research Center (CNIO)
Natarajan Kannan: University of Georgia
Marta Llimargas: Institute of Molecular Biology of Barcelona (IMBB) CSIC
Javier Muñoz: Spanish National Cancer Research Center (CNIO)
Iván Plaza-Menacho: Spanish National Cancer Research Center (CNIO)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Autophosphorylation controls the transition between discrete functional and conformational states in protein kinases, yet the structural and molecular determinants underlying this fundamental process remain unclear. Here we show that c-terminal Tyr 530 is a de facto c-Src autophosphorylation site with slow time-resolution kinetics and a strong intermolecular component. On the contrary, activation-loop Tyr 419 undergoes faster kinetics and a cis-to-trans phosphorylation switch that controls c-terminal Tyr 530 autophosphorylation, 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 Tyr 530 intermolecular autophosphorylation. In an asymmetric arrangement of both catalytic domains, a c-terminal palindromic phospho-motif flanking Tyr 530 on the substrate molecule engages the G-loop of the active kinase adopting a position ready for entry into the catalytic cleft. Perturbation of the phospho-motif accounts for c-Src dysfunction as indicated by viral and colorectal cancer (CRC)-associated c-terminal deleted variants. We show that c-terminal residues 531 to 536 are required for c-Src Tyr 530 autophosphorylation, and such a detrimental effect is caused by the substrate molecule inhibiting allosterically the active kinase. Our work reveals a crosstalk between the activation and c-terminal segments that control the allosteric interplay between substrate- and enzyme-acting kinases during autophosphorylation.

Date: 2023
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DOI: 10.1038/s41467-023-41890-7

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