title: Molecular dynamics of the membrane-talin-vinculin axis under force
creator: Franz, Florian Sebastian
subject: ddc-530
subject: 530 Physics
description: Most multi-cellular organisms depend on adhesion mechanisms to provide stability and a pathway for the transduction of information between cells and the extra cellular matrix. Tissue cells can sense and react to the mechanical properties of their local environment which can steer cellular proliferation, migration, as well as differentiation in stem cells. Focal Adhesions are multi-protein assemblies that constitute the mechanosensitive link between ECM and the actin cytoskeleton. Two major FA proteins, talin and vinculin, exhibit an auto-inhibited conformation in the cytoplasm, yet the molecular process that regulates their activation and allows them to unfold their full signalling potential remains widely unknown.    Using extensive molecular dynamics (MD) simulations we reveal a mechanism by which a flexible loop on the talin FERM domain serves as a first contact point with PIP2 lipids in the cellular membrane and subsequently promotes membrane interactions that can compete with the autoinhibitory link to the talin rod domain. We demonstrate that a variety of vinculin binding sites in the talin rod bind to vinculin in a highly force-regulated manner. We describe on an atomistic level a mechanism in which VBS-binding competes with the autoinhibitory link to the vinculin tail, which was corroborated by a collaborator in magnetic tweezers experiments. Lastly, force-probe MD simulations helped to identify the residues involved in the VBS-induced weakening of the vinculin head-tail interface, facilitating protein activation. With this, we propose two novel vinculin mutants that mimic the effect of talin association and show significantly increased interactions with actin -- comparable to VBS-activated wild-type vinculin -- in experiments carried out by collaboration partners.    Summarized, our findings provide novel insights into the molecular underlying of talin and vinculin activation which help to improve our understanding of hierarchical FA maturation and mechanotransduction.
date: 2021
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/30799/1/Dissertation_Franz.pdf
identifier: DOI:10.11588/heidok.00030799
identifier: urn:nbn:de:bsz:16-heidok-307993
identifier:   Franz, Florian Sebastian  (2021) Molecular dynamics of the membrane-talin-vinculin axis under force.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/30799/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng