Conformational Dynamics of FERM-Mediated Autoinhibition in Pyk2 Tyrosine Kinase.
Hanna S LovingEric S UnderbakkePublished in: Biochemistry (2019)
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.
Keyphrases
- tyrosine kinase
- epidermal growth factor receptor
- protein kinase
- cell migration
- mass spectrometry
- transcription factor
- genome wide
- molecular dynamics simulations
- gene expression
- cystic fibrosis
- high resolution
- dna methylation
- binding protein
- hepatitis c virus
- induced apoptosis
- oxidative stress
- rna seq
- staphylococcus aureus
- multiple sclerosis
- copy number
- human immunodeficiency virus
- hiv infected
- amino acid
- biofilm formation
- endoplasmic reticulum stress
- candida albicans