E41K mutation activates Bruton's tyrosine kinase by stabilizing an inositol hexakisphosphate-dependent invisible dimer.

Autor: Chowdhury S; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Chakraborty MP; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Roy S; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Dey BP; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Gangopadhyay K; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India., Das R; Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur, India; Centre for Advanced Functional Materials, Indian Institute of Science Education and Research Kolkata, Mohanpur, India. Electronic address: rahul.das@iiserkol.ac.in.
Jazyk: angličtina
Zdroj: The Journal of biological chemistry [J Biol Chem] 2024 Aug; Vol. 300 (8), pp. 107535. Date of Electronic Publication: 2024 Jul 04.
DOI: 10.1016/j.jbc.2024.107535
Abstrakt: Bruton's tyrosine kinase (BTK) regulates diverse cellular signaling of the innate and adaptive immune system in response to microbial pathogens. Downregulation or constitutive activation of BTK is reported in patients with autoimmune diseases or various B-cell leukemias. BTK is a multidomain protein tyrosine kinase that adopts an Src-like autoinhibited conformation maintained by the interaction between the kinase and PH-TH domains. The PH-TH domain plays a central role in regulating BTK function. BTK is activated by binding to PIP 3 at the plasma membrane upon stimulation by the B-cell receptor (BCR). The PIP 3 binding allows dimerization of the PH-TH domain and subsequent transphosphorylation of the activation loop. Alternatively, a recent study shows that the multivalent T-cell-independent (TI) antigen induces BCR response by activating BTK independent of PIP 3 binding. It was proposed that a transiently stable IP 6 -dependent PH-TH dimer may activate BTK during BCR activation by the TI antigens. However, no IP 6 -dependent PH-TH dimer has been identified yet. Here, we investigated a constitutively active PH-TH mutant (E41K) to determine if the elusive IP 6 -dependent PH-TH dimer exists. We showed that the constitutively active E41K mutation activates BTK by stabilizing the IP 6 -dependent PH-TH dimer. We observed that a downregulating mutation in the PH-TH domain (R28H) linked to X-linked agammaglobulinemia impairs BTK activation at the membrane and in the cytosol by preventing PH-TH dimerization. We conclude that the IP 6 dynamically remodels the BTK active fraction between the membrane and the cytoplasm. Stimulating with IP 6 increases the cytosolic fraction of the activated BTK.
Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: