Date of Award
Master of Science
Biochemistry, Biophysics and Molecular Biology
Julien F. Roche
Many mental health disorders such as schizophrenia, bipolar disorders, and recurrent major depression have a common significant genetic risk factor called Disrupted-In-Schizophrenia-1 (or DISC1) which codes for an 854-amino acid protein. Because of the lack of structural informa- tion of the protein product of this gene, the molecular mechanisms underlying these conditions remain elusive. DISC1 is an oligomeric protein that was found to be expressed in neurons and glia and localized in many subcellular compartments such as synapses, nuclei, centrosomes, mi- tochondria, and endoplasmic reticula. With over 158 interactors identified by yeast two-hybrid, DISC1 appears to function as a scaffolding hub to assemble multiple proteins into functional units. Pos-translational modifications have also been known to play an essential role in regulating DISC1 activity and its oligomerization state. Particularly, the PKA-induced phosphorylation at S58 has been shown to prevent the interaction with ATF4 and phosphorylation at S713 has been shown to abolish the interaction with GSK3β. In this work, we showed that phosphorylation at S713 affects the oligomeric state of the protein by inducing a conformational change of the protein using size exclusion chromatography and HDX-MS. We found that the phosphomimetic mutant S713 is not a good replacement for the actual phosphorylated DISC598 because it showed little change in con- formation. We also provided in vitro evidence for the interaction of DISC1 with the transcription factor ATF4.
Luan Minh Nguyen
Nguyen, Luan Minh, "Conformational change upon phosphorylation at S713 site of Disrupted-in-schizophrenia-1 (DISC1) leads to a change in the oligomeric state" (2019). Graduate Theses and Dissertations. 17527.