Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.

Abstract:

Cellular mechanosensing is pivotal for virtually all biological processes, and many molecular mechano-sensors and their way of function are being uncovered. In this work, we suggest that c-Src kinase acts as a direct mechano-sensor. c-Src is responsible for, among others, cell proliferation, and shows increased activity in stretched cells. In its native state, c-Src has little basal activity, because its kinase domain binds to an SH2 and SH3 domain. However, it is known that c-Src can bind to p130Cas, through which force can be transmitted to the membrane. Using molecular dynamics simulations, we show that force acting between the membrane-bound N-terminus of the SH3 domain and p130Cas induces partial SH3 unfolding, thereby impeding rebinding of the kinase domain onto SH2/SH3 and effectively enhancing kinase activity. Forces involved in this process are slightly lower or similar to the forces required to pull out c-Src from the membrane through the myristoyl linker, and key interactions involved in this anchoring are salt bridges between negative lipids and nearby basic residues in c-Src. Thus, c-Src appears to be a candidate for an intriguing mechanosensing mechanism of impaired kinase inhibition, which can be potentially tuned by membrane composition and other environmental factors.

SEEK ID: https://publications.h-its.org/publications/1453

PubMed ID: 35120901

DOI: 10.1016/j.bpj.2022.01.028

Research Groups: Molecular Biomechanics

Publication type: Journal

Journal: Biophysical Journal

Publisher: Elsevier BV

Citation: Biophys J,121(5):684-691

Date Published: 2nd Feb 2022

URL:

Registered Mode: manually

Authors: Csaba Daday, Svenja de Buhr, Davide Mercadante, Frauke Gräter

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Citation
Daday, C., de Buhr, S., Mercadante, D., & Gräter, F. (2022). Mechanical force can enhance c-Src kinase activity by impairing autoinhibition. In Biophysical Journal (Vol. 121, Issue 5, pp. 684–691). Elsevier BV. https://doi.org/10.1016/j.bpj.2022.01.028
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Created: 21st Feb 2022 at 02:28

Last updated: 5th Mar 2024 at 21:24

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