Conformational Dynamics of FERM-Mediated Autoinhibition
in Pyk2 Tyrosine Kinase
Posted on 2019-08-22 - 17:03
Pyk2
is a non-receptor tyrosine kinase that evolved from gene duplication
of focal adhesion kinase (FAK) and subsequent functional specialization
in the brain and hemopoietic cells. Pyk2 shares a domain organization
with FAK, with an N-terminal regulatory FERM domain adjoining the
kinase domain. FAK regulation involves integrin-mediated membrane
clustering to relieve autoinhibitory interactions between FERM and
kinase domains. Pyk2 regulation remains cryptic, involving Ca2+ influx and protein scaffolding. While the mechanism of the
FAK FERM domain in autoinhibition is well-established, the regulatory
role of the Pyk2 FERM is ambiguous. We probed the mechanisms of FERM-mediated
autoinhibition of Pyk2 using hydrogen/deuterium exchange mass spectrometry
and kinase activity profiling. The results reveal FERM–kinase
interfaces that are responsible for autoinhibition. Pyk2 autoinhibition
impacts the activation loop conformation. In addition, the autoinhibitory
FERM–kinase interface exhibits allosteric linkage with the
FERM basic patch conserved in both FAK and Pyk2.
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Loving, Hanna
S.; Underbakke, Eric S. (2019). Conformational Dynamics of FERM-Mediated Autoinhibition
in Pyk2 Tyrosine Kinase. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.9b00541
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AUTHORS (2)
HL
Hanna
S. Loving
EU
Eric S. Underbakke
KEYWORDS
FAK regulationConformational DynamicsFERM domainnon-receptor tyrosine kinaseprotein scaffoldingFERM-Mediated Autoinhibitionkinase domainsactivation loop conformationPyk 2 autoinhibition impactsintegrin-mediated membranehemopoietic cellsFAK FERM domainPyk 2 Tyrosine Kinase Pyk 2FERM-mediated autoinhibitionkinase domaindomain organizationautoinhibitory interactionsPyk 2 sharesgene duplicationkinase activityPyk 2Pyk 2 FERMPyk 2 regulationadhesion kinase