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Molecular interactions of bruton's tyrosine kinase

Cory, Giles Oliver Cholmondeley; (1997) Molecular interactions of bruton's tyrosine kinase. Doctoral thesis (Ph.D.), University College London (United Kingdom). Green open access

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Abstract

X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency disorder characterised by a dramatic reduction in the numbers of peripheral B cells and immunoglobulins of all isotypes. Patients exhibit a selective impairment of B cell development with other haematopoietic cell lineages remaining unaffected. XLA is caused by mutations in the BTK gene which encodes the cytoplasmic protein, Bruton's tyrosine kinase (Btk). Evidence suggests that Btk is involved in the transduction of signals in both developing and mature B cells. Btk is a modular molecule, consisting of several well defined protein domains. These include a Src homology (SH) 1 domain containing the catalytic activity, an SH2, an SH3 and a Pleckstrin homology (PH) domain, all of which are believed to mediate distinct types of inter and intramolecular interactions. In order to understand Btk's function in the signalling network of the B cell it is necessary to understand the interactions of its domains and to identify their ligands. This thesis describes an in vitro dissection of Btk's molecular interactions. Btk's protein domains were expressed separately in the form of recombinant fusion proteins and used to probe B cell lysates to affinity purify their preferred ligands. Two ligands for the SH3 domain of Btk were identified, c-Cbl and WASP (the protein mutated in the primary immunodeficiency Wiskott-Aldrich syndrome). Further investigations showed that c-Cbl became rapidly tyrosine phosphorylated following cross-linking of the B cell antigen receptor (BCR), suggesting a role in early signalling events. WASP was shown to bind the Btk SH3 domain in abundance. Competition experiments using peptides derived from WASP identified the regions within WASP likely to be bound by the SH3 domain. c-Cbl and WASP are the first ligands to be described for the SH3 domain of Btk. These results implicate c-Cbl, WASP and Btk in common lymphocyte signalling pathways.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: Molecular interactions of bruton's tyrosine kinase
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: (UMI)AAIU108352; Health and environmental sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10102013
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