Understanding IP₆ mediated dimer of Bruton’s Tyrosine Kinase and its Activation

Acharya, Ananya (2017) Understanding IP₆ mediated dimer of Bruton’s Tyrosine Kinase and its Activation. Masters thesis, Indian Institute of Science Education and Reseach Kolkata.

PDF (MS dissertation of Ananya Acharya (12MS076)) Ananya_Acharya_Thesis.pdf - Submitted Version Restricted to Repository staff only Download (2MB)

Abstract

Bruton’s tyrosine kinase (Btk) is a non-receptor tyrosine kinase required for regulation of B-lymphocyte development, differentiation and signalling. Deregulation of Btk signalling leads to cancer and immunodeficiency diseases like X-linked agammaglobulinemia (XLA) for human and X-linked immunodeficiency (Xid) for mice. Btk is composed of an N-terminal Pleckstrin and Tec homology domain (PH-TH), Src homology 2 and 3 (SH₂ and SH₃) domains and the C-terminal tyrosine kinase domain. Btk is known to be activated by its localization to the plasma membrane and subsequent phosphorylation by Src family of kinases. Recently, it was found that inositol hexakisphosphate (IP₆) activates Btk by binding to the PH-TH domain, even in the absence of a membrane. This may represent an alternate mechanism of activation of Btk. The detailed structural and functional significance of Btk activation by IP₆ is still unknown. The E41K substitution mutation in the PH-TH domain constitutively activates Btk. This activating mutant also shows higher affinity for IP₆ than the wild type Btk emphasising the central role of IP₆ in Btk regulation. In this study, we will focus our efforts to understand the role of IP₆ in regulation of Btk and it’s constitutively activated mutant E41K using Dynamic Light Scattering and Size Exclusion Chromatography.

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