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|Title:||Identification of residues involved in NS2 homodimerization and elucidation of their impact on the HCV life cycle|
|Citation:||Journal of Viral Hepatitis, 2012; 19(3):189-198|
|Publisher:||Blackwell Science Ltd|
|A. A. Gorzin, P. A. Ramsland, G. Tachedjian, and E. J. Gowans|
|Abstract:||The NS2 protein of hepatitis C virus (HCV) plays a critical role in virus morphogenesis and infectivity. The crystal structure of the C-terminus of the NS2 protein (NS2Pro) from the H77 strain indicates that NS2Pro forms a homodimer. In this study, using computational modelling, we identified residues at the NS2Pro dimer interface that have a role in dimerization and confirmed their capacity to influence dimerization by expression studies. Our modelling analysis identified 22 residues at the NS2Pro dimer interface that may be important for dimer formation. Based on the free binding energy, we selected the top five ranked mutations (V162A, M170A, I175A, D186A and I201A) for further study. Western blot analysis revealed that M170A, I175A, I201A, D186A and V162A resulted in a 4.0-, 3.2-, 3.0-, 2.8- and 1.5-fold increase, respectively, in the monomer/dimer ratio compared to wild type, confirming a role in homodimer formation or stability. Japanese Fulminant Hepatitis type 1 mutants expressing M170A, I175A, D186A and I201A demonstrated increasing defects in both RNA replication and the production of infectious virus compared to wild type. This study identified residues at the NS2Pro dimer interface that modulate NS2Pro homodimerization and demonstrated that abrogation of NS2Pro homodimerization results in defects in HCV replication and release of infectious virus.|
hepatitis C virus
Japanese Fulminant Hepatitis type 1
|Rights:||© 2011 Blackwell Publishing Ltd|
|Appears in Collections:||Aurora harvest|
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