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

Author

Listed:
  • 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)
    Universidad Francisco de Vitoria (UFV))

  • 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)
    IIS Biocruces Bizkaia)

  • Iván Plaza-Menacho

    (Spanish National Cancer Research Center (CNIO))

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.

Suggested Citation

  • Hipólito Nicolás Cuesta-Hernández & Julia Contreras & Pablo Soriano-Maldonado & Jana Sánchez-Wandelmer & Wayland Yeung & Ana Martín-Hurtado & Inés G. Muñoz & Natarajan Kannan & Marta Llimargas & Javie, 2023. "An allosteric switch between the activation loop and a c-terminal palindromic phospho-motif controls c-Src function," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41890-7
    DOI: 10.1038/s41467-023-41890-7
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    References listed on IDEAS

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    1. Christina Curtis & Sohrab P. Shah & Suet-Feung Chin & Gulisa Turashvili & Oscar M. Rueda & Mark J. Dunning & Doug Speed & Andy G. Lynch & Shamith Samarajiwa & Yinyin Yuan & Stefan Gräf & Gavin Ha & Gh, 2012. "The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups," Nature, Nature, vol. 486(7403), pages 346-352, June.
    2. Peter Blume-Jensen & Tony Hunter, 2001. "Oncogenic kinase signalling," Nature, Nature, vol. 411(6835), pages 355-365, May.
    3. Wenqing Xu & Stephen C. Harrison & Michael J. Eck, 1997. "Three-dimensional structure of the tyrosine kinase c-Src," Nature, Nature, vol. 385(6617), pages 595-602, February.
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