Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase
- Charles University, Czech Republic
Abstract
The activation of Src kinase in cells is strictly controlled by intramolecular inhibitory interactions mediated by SH3 and SH2 domains. They impose structural constraints on the kinase domain holding it in a catalytically non‑permissive state. The transition between inactive and active conformation is known to be largely regulated by the phosphorylation state of key tyrosines 416 and 527. Here we identified that phosphorylation of tyrosine 90 reduces binding affinity of the SH3 domain to its interacting partners, opens the Src structure, and renders Src catalytically active. This is accompanied by an increased affinity to the plasma membrane, decreased membrane motility and slower diffusion from focal adhesions. Phosphorylation of tyrosine 90 controlling SH3‑medited intramolecular inhibitory interaction, analogical to tyrosine 527 regulating SH2‑C‑terminus bond, enables SH3 and SH2 domains to serve as cooperative but independent regulatory elements. This mechanism allows Src to adopt several distinct conformations of varying catalytic activities and interacting properties, enabling it to operate not as a simple switch but as a tunable regulator functioning as a signaling hub in a variety of cellular processes.
Data availability
All data generated or analysed during this study are included in the manuscript and supplementary figures. Source Data files have been provided for Figures 1-7.
Article and author information
Author details
Funding
Grantová Agentura České Republiky (19-03932S)
- Lenka Koudelková
- Jan Brábek
- Daniel Rösel
Ministerstvo Školství, Mládeže a Tělovýchovy (LX22NPO5102)
- Lenka Koudelková
- Markéta Pelantová
- Jan Brábek
- Daniel Rösel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kathleen Gould, Vanderbilt University, United States
Version history
- Received: August 3, 2022
- Preprint posted: August 24, 2022 (view preprint)
- Accepted: July 7, 2023
- Accepted Manuscript published: July 10, 2023 (version 1)
- Version of Record published: July 21, 2023 (version 2)
Copyright
© 2023, Koudelková et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Phosphorylation of tyrosine 90 in SH3 domain is a new regulatory switch controlling Src kinase
eLife 12:e82428.
https://doi.org/10.7554/eLife.82428
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