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PDBsum entry 4d58
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References listed in PDB file
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Key reference
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Title
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Allosteric regulation of focal adhesion kinase by pipâ‚‚ and ATP.
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Authors
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J.Zhou,
A.Bronowska,
J.Le coq,
D.Lietha,
F.Gräter.
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Ref.
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Biophys J, 2015,
108,
698-705.
[DOI no: ]
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PubMed id
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Abstract
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Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that regulates cell
signaling, proliferation, migration, and development. A major mechanism of
regulation of FAK activity is an intramolecular autoinhibitory interaction
between two of its domains-the catalytic and FERM domains. Upon cell adhesion to
the extracellular matrix, FAK is being translocated toward focal adhesion sites
and activated. Interactions of FAK with phosphoinositide
phosphatidylinsositol-4,5-bis-phosphate (PIP2) are required to activate FAK.
However, the molecular mechanism of the activation remains poorly understood.
Recent fluorescence resonance energy transfer experiments revealed a closure of
the FERM-kinase interface upon ATP binding, which is reversed upon additional
binding of PIP2. Here, we addressed the allosteric regulation of FAK by
performing all-atom molecular-dynamics simulations of a FAK fragment containing
the catalytic and FERM domains, and comparing the dynamics in the absence or
presence of ATP and PIP2. As a major conformational change, we observe a closing
and opening motion upon ATP and additional PIP2 binding, respectively, in good
agreement with the fluorescence resonance energy transfer experiments. To reveal
how the binding of the regulatory PIP2 to the FERM F2 lobe is transduced to the
very distant F1/N-lobe interface, we employed force distribution analysis. We
identified a network of mainly charged residue-residue interactions spanning
from the PIP2 binding site to the distant interface between the kinase and FERM
domains, comprising candidate residues for mutagenesis to validate the predicted
mechanism of FAK activation.
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