Crystallization of GSK3β with an inhibiting peptide of psychiatric risk factor DISC1
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Disrupted in Schizophrenia 1 (DISC1) is a candidate risk gene in several major mental illnesses, e.g. depression, bipolar disorder, and schizophrenia. The full-length DISC1 protein comprises of 854 amino acids. It is a scaffold protein that interacts with a very large number of other proteins, forming a sizeable protein-protein-interaction network that coordinates various stages of brain development. One of those important interactors is the enzyme, glycogen synthase kinase 3β (GSK3β). As a target for lithium, GSK3β itself is implicated in bipolar disorder. The interaction of DISC1 and GSK3β was discovered at the cross-section of the canonical Wnt/β-catenin signalling which controls the proliferation of neural progenitors. DISC1 specifically inhibits GSK3β’s function in this pathway via a direct physical interaction. GSK3β is involved with the Axin-APC complex in this pathway, and its main role is to phosphorylate and regulate the levels of β-catenin in the cell which in turn is a regulator of gene expression levels. The most potent GSK3 inhibitory region has been mapped to a small region in the N-terminus (residue 195-238) of DISC1. This 44-amino acid region (hD1) inhibits GSK3 in an ATP non-competitive mechanism and its binding site partially overlap with that of a peptide from another GSK3β binding protein, FRATide. Knowledge regarding the molecular network of the interactions between hD1, FRATide, and GSK3β remains elusive. This thesis focusses on the effort towards obtaining crystals for the protein complexes GSK3β-hD1 and GSK-hD1-FRATide. Crystals of the putative binary and ternary protein complexes were successfully obtained.
DegreeMaster of Science (M.Sc.)
DepartmentVeterinary Biomedical Sciences
ProgramVeterinary Biomedical Sciences
SupervisorLeung, Adelaine K. W.
CommitteeSanders, David; Cygler, Miroslaw; Adams, Gregg
Copyright DateAugust 2020