Biophysical Society Thematic Meeting | Hamburg 2022

Biophysics at the Dawn of Exascale Computers

Poster Abstracts

17-POS Board 17 MECHANICAL FORCE CAN ENHANCE C-SRC KINASE ACTIVITY Csaba Daday 1 ; Svenja de Buhr 1 ; Davide Mercadante 1 ; Frauke Gräter 1,2 ; 1 Heidelberg Institute for Theoretical Studies, Heidelberg, Germany 2 Heidelberg University, Interdisciplinary Center for Scientific Computing (IWR), Heidelberg, Germany Mechano-sensing proteins are crucial for cellular function since they translate physical cues from the environment to biochemical signaling cascades. Src kinase is involved in a plethora of pathways including cell proliferation and migration. It is a well known player in force transduction pathways and we asked whether it is directly activated by force. In its resting state the kinase domain is auto-inhibited by the SH2 and SH3 domains. Src can be tethered to the cellular membrane through an N-terminal myristoylation and to the cytoskeleton by binding to the adaptor protein p130Cas. We used Molecular Dynamics simulations to mimic forces transmitted to the N-terminus of the SH3 domain and a Src-bond p130Cas peptide to investigate a possible mechano-activating mechanism. Force resulted in partial unfolding of the SH3 domain and therefore enhances kinase activity by impeding re-binding of the SH3/SH2 domains. Furthermore, we tested the mechanical stability of membrane binding, for which electrostatic interactions between negatively charged lipids and positively charged residues on the myristoyl linker are essential. The forces required to rupture the Src membrane anchor are similar or slightly higher than those needed for SH3-domain unfolding. Thus, Src is an intriguing candidate for a mechano-sensing protein, which might be tuned by factors such as cellular ion or membrane composition.

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