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

• Verfasst von: Daday, Csaba [VerfasserIn]
• Verfasst von: Buhr, Svenja de [VerfasserIn]
• Verfasst von: Mercadante, Davide [VerfasserIn]
• Verfasst von: Gräter, Frauke [VerfasserIn]
• Titel: Mechanical force can enhance c-Src kinase activity by impairing autoinhibition
• Verf.angabe: Csaba Daday, Svenja de Buhr, Davide Mercadante, and Frauke Gräter
• E-Jahr: 2022
• Jahr: 2 February 2022
• Umfang: 8 S.
• Fussnoten: Gesehen am 05.04.2022
• Titel Quelle: Enthalten in: Biophysical journal
• Ort Quelle: Cambridge, Mass. : Cell Press, 1960
• Jahr Quelle: 2022
• Band/Heft Quelle: 121(2022), 5, Seite 684-691
• ISSN Quelle: 1542-0086
• DOI: doi:10.1016/j.bpj.2022.01.028
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1797310828

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.