Genetic effects on immunity

Bruton's tyrosine kinase (Btk), a cytoplasmic protein-tyrosine kinase, plays a pivotal role in B cell activation and development. Mutations in the pleckstrin homology (PH) domain of the Btk gene cause human X-linked agammaglobulinemia (XLA) and murine X-linked immunodeficiency (Xid). In this paper, we report that the PH domain of Btk functions as an inositol 1,3,4,5-tetrakisphosphate (IP4), inositol 1,3,4,5,6-pentakisphosphate, and inositol 1,2,3,4,5,6-hexakisphosphate (IP6) binding domain (Kd of approximately 40 nM for IP4), and that all of the XLA (Phe replaced by Ser at position 25 (F25S), R28H, T33P, V64F, and V113D) and Xid mutations (R28C) found in the PH domain result in a dramatic reduction of IP4 binding activity. Furthermore, the rare alternative splicing variant, with 33 amino acids deleted in the PH domain, corresponding to exon 3 of the Btk gene, also impaired IP4 binding capacity. In contrast, a gain-of-function mutant called Btk*, which carries a E41K mutation in the PH domain, binds IP6 with two times higher affinity than the wild type. Our data suggest that B cell differentiation is closely correlated with the IP4 binding capacity of the PH domain of Btk.

Pleckstrin homology domain

10.1074/jbc.271.48.30303

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Citations (204)

Molecular and Structural Characterization of Five Novel Mutations in the Bruton’s Tyrosine Kinase Gene from Patients with X-Linked Agammaglobulinemia

Molecular Medicine (1997)

Bratin K. Saha Sherill K. Curtis Larry B. Vogler Mauno Vihinen

X-linked agammaglobulinemia

Human genetics

10.1007/bf03401694

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Citations (21)

Bruton's Tyrosine Kinase (BTK) is present in normal platelets, and its absence identifies patients with X-Linked Agammaglobulinemia (XLA) and carrier females

Chiaki Watanabe Takeshi Futatani Yoshihiro Baba Satoshi Tsukada A. Oda

Bruton's Tyrosine Kinase (BTK) Is Present in Normal Platelets, and Its Absence Identifies Patients with X-Linked Agammaglobulinemia (XLA) and Carrier Females

X-linked agammaglobulinemia

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Citations (0)

Newly diagnosed X-linked agammaglobulinemia (XLA), bruton's tyrosine kinase (Btk) mutation, in a 39 year-old male

Journal of Allergy and Clinical Immunology (2002)

Sean R Bulley J Zhang Suzanna Kwong Chaim M. Roifman

X-linked agammaglobulinemia

10.1016/s0091-6749(02)81694-3

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Citations (4)

Lipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases

Proceedings of the National Academy of Sciences (2019)

Neha Amatya Thomas E. Wales Annie Kwon Wayland Yeung R Joseph

Significance Bruton’s tyrosine kinase (BTK) is targeted in treatment of immune cancers. As patients experience drug resistance, there is a need for alternative approaches to inhibit BTK. Other recently published findings clarify the role of the BTK pleckstrin homology (PH) domain in mediating activation via dimerization and sensing of ligand concentration at the membrane. Work presented here provides insight into the autoinhibitory BTK structure that has so far been elusive via crystallographic methods. In the resting state, the BTK PH domain binds to the activation loop face of the kinase domain and allosterically alters key sites within the kinase domain. The findings define a new regulatory site, the PH/kinase interface, that can be exploited in drug discovery efforts.

Pleckstrin homology domain

Protein kinase domain

10.1073/pnas.1907566116

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Citations (25)

Crystal structure of the Bruton’s tyrosine kinase PH domain with phosphatidylinositol

Biochemical and Biophysical Research Communications (2008)

Kazutaka Murayama M. Kato-Murayama Chiemi Mishima Ryogo Akasaka Mikako Shirouzu

Pleckstrin homology domain

Protein kinase domain

10.1016/j.bbrc.2008.09.055

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Citations (18)