ArticleBiochemistry2011
Controlling the activity of the Tec kinase Itk by mutation of the phenylalanine gatekeeper residue.
Article in Biochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 18 citations in OpenAlex.
- Stereoselective Covalent Targeting of BTK(C481S) and Kinases with β-Lactone Electrophiles.bioRxiv : the preprint server for biology · 2026Article
- A New Mechanism of Supraventricular Tachycardia: Gene Mutation.Current cardiology reviews · 2025Review
- Outer coordination sphere influences on cofactor maturation and substrate oxidation by cytochrome P460.Chemical science · 2023Article
- Role of non-coding variants in cardiovascular disease.Journal of cellular and molecular medicine · 2023Review
- Calculation of centralities in protein kinase A.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Article
- Chemical genetic identification of GAK substrates reveals its role in regulating NaLife science alliance · 2018Article
- Allele-sensitive mutant, Itkas, reveals that Itk kinase activity is required for Th1, Th2, Th17, and iNKT-cell cytokine production.European journal of immunology · 2015Article
- Whole exome sequencing identifies the TNNI3K gene as a cause of familial conduction system disease and congenital junctional ectopic tachycardia.International journal of cardiology · 2015Article
- A conserved isoleucine maintains the inactive state of Bruton's tyrosine kinase.Journal of molecular biology · 2014Article
- Deciphering the structural basis of eukaryotic protein kinase regulation.PLoS biology · 2013Article
- Design principles underpinning the regulatory diversity of protein kinases.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2012Review
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Authors and funding
2 authors at 1 institution in 1 country.
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Abstract
The regulatory spine is a set of conserved residues that are assembled and disassembled upon activation and inactivation of kinases. We recently identified the regulatory spine within the immunologically important Tec family kinases and have shown that in addition to the core spine residues within the kinase domain itself, contributions from the SH2-kinase linker region result in an extended spine structure for this kinase family. Disruption of the regulatory spine, either by mutation or by removal of the amino-terminal SH2-kinase linker region or by mutation of core spine residues, leads to inactivation of the Tec kinases. With a focus on the Tec family members, Itk and Btk, we now show that the gatekeeper residue is also critical for the assembly of the regulatory spine. Mutation of the bulky Itk F434 gatekeeper residue to alanine or glycine inactivates Itk. The activity of the Itk F434A mutant can be recovered by a secondary site mutation within the N-terminal lobe, specifically L432I. The Itk L432I mutation likely rescues the activity of the gatekeeper F434A mutation by promoting the assembly of the regulatory spine. We also show that mutation of the Itk and Btk gatekeeper residues to methionine is sufficient to activate the isolated kinase domains of Tec kinases in the absence of the amino-terminal SH2-kinase linker. Thus, shifting the conformational equilibrium between the assembled and disassembled states of the regulatory spine by changing the nature of the gatekeeper residue is key to regulating the activity of Tec kinases.
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