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%0 Thesis
%A Haan, Claude
%T Untersuchungen zur gp130/Jak1-Interaktion
%C Aachen
%I Publikationsserver der RWTH Aachen University
%M RWTH-CONV-123007
%P IV, 83 S. : Ill., graph. Darst.
%D 2000
%Z Aachen, Techn. Hochsch., Diss., 2000
%X The common receptor subunit gp130 is essential for cellular responses following stimulation with IL-6-type cytokines. Signal transduction via gp130 occurs through activation of constitutively associated kinases of the Janus family (Jak1, Jak2 and Tyk2). Since Jak1 plays the most important role the interaction of gp130 with Jak1 was investigated by means of mutagenesis of both molecules. The minimal binding region of Jak1 to gp130 was restricted to the membrane proximal 68 amino acids. W666 and Box2 were shown to be crucial for Jak binding and further signal transduction. Interestingly, the amino acid exchanges W652A, P671A/P672A and F676A showed that Jak1 binding is necessary but not sufficient for STAT activation. Amino acid exchanges were also introduced into the N-terminal domain of Jak1 and the binding of Jak1 to gp130 was examined using a coimmunoprecipitation assay. A structure prediction model postulating a b-grasp domain in Jak1 was verified using a mutagenesis aproach. Mutations L80A, L80A/Y81A and Y81A/D82A induce the loss of Jak1 binding to gp130. These mutants are located in loop 4 between two b-strands in the predicted b-grasp-model indicating that this region is crucial for Jak1 binding to gp130. Exchange of Y107 to alanine also abrogates Jak1 association to the receptor and was predicted to be structurally important in the b -grasp-model.
%F PUB:(DE-HGF)11
%9 Dissertation / PhD Thesis
%U https://publications.rwth-aachen.de/record/61334