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The novel synaptic scaffold protein--SHANK

Authors Kan, Ho Man
Issue Date 2002
Summary Shank family proteins are a class of newly discovered neuronal scaffold proteins. Full-length Shank contains, from its amino-to carboxyl-end, multiple ankyrin repeats, an SH3 domain, a PDZ domain, a long proline-rich region, and a SAM domain. Each of these domains can act as a docking site for neuronal proteins via specific protein-protein interactions. For example, Shank is known to interact with three major classes of glutamate receptors (the N-methyl-D-aspartate receptor, the metabotropic Glutamate Receptor and the Alpha-amino-3-hydroxy-5-Methyl-4-isoxazole-Proprionic Acid Receptor). Due to lack of detailed biochemical and structural characterization of the various domains of Shank, the molecular basis of Shank-mediated protein interaction is largely unknown. The work of this thesis focuses on the biochemical and structural properties of the SH3 and PDZ domains of Shank. In this thesis research, an efficient expression and purification scheme was developed for obtaining large quantities of recombinant SH3 and PDZ domains of Shank. The work laid a foundation for high resolution structure determination of the domains by NMR spectroscopic techniques. The high resolution structure of the Shank SH3 domain shows that the domain contains an extra ordered N-terminal fragment that is not observed in the structure of other known SH3 domains. The structure of the Shank SH3 domain suggests that the N-terminal fragment may function as a regulatory element of the Shank SH3 domain by influencing its target-binding capacities. We further show that the SH3 domain and the PDZ domain of Shank interact with each other. Detailed biochemical analysis indicated that the association of the two domains is intramolecular in nature. It is possible that the SH3 domain is kept in an auto-inhibited conformation by such inter-domain interaction. The data presented in this thesis provide insights into the biochemical basis of the SH3- PDZ domain-mediated target interaction of Shank proteins.
Note Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2002
Language English
Format Thesis
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