Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/47510
Title: STRUCTURAL BASIS FOR ANCHORING HCV REPLICATION COMPLEX ONTO THE HUMAN ER-MEMBRANE: IMPLICATIONS FOR HCV-TRIGGERED ALS PATHOGENESIS
Authors: GARVITA GUPTA
Keywords: HCV,NS5A Protein,NS5B protein,VAPB protein,Eph Receptor,Amyotrophic lateral sclerosis,fuzzy complex
Issue Date: 25-Jan-2013
Source: GARVITA GUPTA (2013-01-25). STRUCTURAL BASIS FOR ANCHORING HCV REPLICATION COMPLEX ONTO THE HUMAN ER-MEMBRANE: IMPLICATIONS FOR HCV-TRIGGERED ALS PATHOGENESIS. ScholarBank@NUS Repository.
Abstract: Hepatitis C virus (HCV) affects nearly 200 million people worldwide and is a leading factor for serious chronic liver diseases. Replication of HCV genome occurs on membrane associated replication complex, which is formed by the interaction of HCV non-structural proteins including NS5A and NS5B, and human host ER membrane protein VAPB. In this thesis work, I have studied these interactions extensively for the first time. Structural characterization of NS5A from HCV genotype 1b S1 strain revealed that domain 3 is intrinsically unstructured domain with some helical propensity at C-terminal region. Systematic interactional studies of NS5A-VAPB demonstrated that C-terminal region of NS5A (NS5A-D3B) forms a ¿fuzzy complex¿ with MSP domain of VAPB with the average dissociation constant of ~5 µM. Binding surface mapping and reduction of interaction affinity with T46I mutant of MSP domain indicated the overlap between Eph receptor and NS5A binding site on MSP domain which was further confirmed by competition binding experiments. These results for the first time indicated the probable mechanism of association between HCV infection and ALS disease. Binding studies of MSP-Eph receptors indicated that all the receptors interact at same surface on MSP domain but with different binding affinity or mode. Furthermore, the interactional studies of NS5B with VAPB revealed that MSP domain of VAPB interacts with NS5B.
URI: http://scholarbank.nus.edu.sg/handle/10635/47510
Appears in Collections:Ph.D Theses (Open)

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