Characterization of the interaction between PSD-95 GK domain and MAP1A

Abstract

Nervous system, mainly composed of large numbers of neurons and glia cells, plays central roles in controlling various physiological functions in the metazoan. The normal functions of nervous system largely depend on the proper connections between neurons through the specialized structure named synapses. A typical glutamatergic synapse contains three parts: a presynaptic region, which releases glutamate as neurotransmitters; a postsynaptic region, which contains glutamate receptors and can be activated by neurotransmitters; and a synaptic cleft between them. The postsynaptic region is a macromolecular network formed by membranes, receptors, scaffold proteins and enzymes in a highly condensed pattern, shows high electron density under electronic microscopes, and is therefore called postsynaptic density (PSD). PSD-95, a member of membrane-associated guanylate kinases (MAGUKs), mediates varieties of protein-protein interactions through its multiple domains, and plays essential roles in the proper PSD functions, dynamics and plasticity. Microtubule-associated protein 1 A (MAP1A) is a microtubule-stabilizer, and participates in activity-driven dendritic arbor remodeling. Previous studies have found that GK domain of PSD-95 can physically interact with MAP1A, but the detailed binding mechanism remains to be elucidated. Studies in this thesis mainly focused on how the MAP1A interacts with PSD-95 GK domain in an unexpected phosphorylation-independent manner. By using X-ray crystallography, the structure of MAP1A peptide and PSD-95 GK complex was solved. MAP1A peptide adopts a folded conformation to interact with GK. The conformation of MAP1A peptide is different from those of previously reported GK-binding peptides such as p-LGN and p-Lgl. The data in this thesis also shows the conformation of the MAP1A peptide might be binding-induced. Finally, these results contribute to better understanding how GK domains of MAGUKs interact with targets with diverse modes, and provide insights into how PSD-95 and MAP1A can work cooperatively in dendritic remodeling.

Date of Award	2014
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology