An Autoinhibitory Role for the Pleckstrin Homology Domain of Interleukin-2-Inducible Tyrosine Kinase and Its Interplay with Canonical Phospholipid Recognition

Biochemistry
Sujan DevkotaA H Andreotti

Abstract

Pleckstrin homology (PH) domains are well-known as phospholipid binding modules, yet evidence that PH domain function extends beyond lipid recognition is mounting. In this work, we characterize a protein binding function for the PH domain of interleukin-2-inducible tyrosine kinase (ITK), an immune cell specific signaling protein that belongs to the TEC family of nonreceptor tyrosine kinases. Its N-terminal PH domain is a well-characterized lipid binding module that localizes ITK to the membrane via phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding. Using a combination of nuclear magnetic resonance spectroscopy and mutagenesis, we have mapped an autoregulatory protein interaction site on the ITK PH domain that makes direct contact with the catalytic kinase domain of ITK, inhibiting the phospho-transfer reaction. Moreover, we have elucidated an important interplay between lipid binding by the ITK PH domain and the stability of the autoinhibitory complex formed by full length ITK. The ITK activation loop in the kinase domain becomes accessible to phosphorylation to the exogenous kinase LCK upon binding of the ITK PH domain to PIP3. By clarifying the allosteric role of the ITK PH domain in controlling ITK function, we have ex...Continue Reading

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Citations

Apr 21, 2018·Annual Review of Immunology·Amy H AndreottiLeslie J Berg
Sep 6, 2018·Critical Reviews in Biochemistry and Molecular Biology·Neel H ShahJohn Kuriyan
Oct 9, 2019·Proceedings of the National Academy of Sciences of the United States of America·Neha AmatyaAmy H Andreotti
Mar 8, 2020·The Journal of Biological Chemistry·Wing Fai LiThomas E Smithgall
May 2, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Enas HallumiDeborah Yablonski
Jul 13, 2021·Frontiers in Cell and Developmental Biology·Lauren E KuefferAmy H Andreotti

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