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primary topic: Focal Adhesion Kinase as a Cellular Mechano-Sensor

Focal Adhesion Kinase as a Cellular Mechano-Sensor
type: Article
abstract: Mechanical signaling plays a crucial role in cell communication. Translating mechanical force into biochemical reactions is vital for virtually all cellular processes such as cell proliferation and differentiation. Mechanosensors, which can respond to an external force in form of controllable conformational changes, are key regulators in the mechanical signal transduction processes. In this work, we present results from Molecular Dynamics (MD) and biochemical network simulations that suggest Focal Adhesion Kinase (FAK) as a mechanosensing enzyme in the signaling pathway. FAK is a non-receptor tyrosine kinase, located at the cytoplasmic site of the cell membrane. During the last decade, a growing body of evidence shows that tensile stress acting on cells leads to increased FAK activity. However, the mechanism of FAK mechanical activation has not been resolved. The auto-inhibitory conformation of the FAK FERMkinase fragment suggests that the major mechanism of the regulation of FAK activity is the release of Tyr576/577 on the activation loop from the N-terminal FERM domain. We first addressed the allosteric regulation of the FAK by PIP2 binding (Chapter 3), a recently recognized stimulus for FAK activation, by performing all-atom MD simulations of FAK FERM-kinase fragment and comparing the dynamics in absence and presence of ATP and PIP2. A closing-opening motion between the kinase and FERM domain upon ATP and additional PIP2 binding was observed in close agreement with corresponding changes in fluorescence resonance energy transfer experiments. As an underlying allosteric mechanism, using Force Distribution Analysis (FDA), a signal network spanning from the PIP2 and ATP binding site to the distant interface between the FERM and kinase domains could be identified. However, our results also demonstrated that the ligand induced conformational changes are insufficient for FAK catalytic turnover, which requires full exposure of Tyr576/577. This suggests that an additional…
date: 2015
author list: authors
type: EPrint
type: DoctoralThesisEPrint
is part of: repository
has document: Focal Adhesion Kinase as a Cellular Mechano-Sensor (PDF)
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subject: 540 Chemie

Focal Adhesion Kinase as a Cellular Mechano-Sensor (PDF)
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Jing Zhou
type: Person
given name: Jing
family name: Zhou

Focal Adhesion Kinase as a Cellular Mechano-Sensor (Other)
type: Document
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Focal Adhesion Kinase as a Cellular Mechano-Sensor (Other)
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Focal Adhesion Kinase as a Cellular Mechano-Sensor (Other)
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Focal Adhesion Kinase as a Cellular Mechano-Sensor (Other)
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Focal Adhesion Kinase as a Cellular Mechano-Sensor (Other)
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primary topic: Focal Adhesion Kinase as a Cellular Mechano-Sensor

540 Chemie
type: Concept
preferred label: 540 Chemistry and allied sciences @en