Thursday, May 7, 2009
Poster @ “Biology and Pathogenesis of viruses: Molecular Insights”, 4th to 5th May,2009,Bangalore, India.
Sudha G and Yamunadevi S from NS group presented a poster on
STRUCTURAL BASIS OF INTERACTION BETWEEN HUMAN CASEIN KINASE 1 ALPHA AND NS5A PEPTIDE FROM HEPATITIS C VIRUS
G. Sudha*, Nidhi Tyagi#, S. Yamunadevi#, Saumitra Das$, N. Srinivasan#.
*School of Biotechnology, Chemical and Biomedical engineering, Vellore institute of Technology University, Tamilnadu. #Molecular Biophysics Unit, $Department of Microbiology and Cell Biology,
Indian Institute of Science, Bangalore.
Background: The non-structural 5A (NS5A) Protein of Hepatitis C virus (HCV) has been the subject of intensive research in recent times. NS5A protein in its basal (p56) and hyper (p58) phosphorylated forms along with human vesicle associated membrane protein A (hvap-A) and other non structural proteins of HCV are shown to regulate HCV replication. Serine2204 of the NS5A protein was reported to be phosphorylated by human casein kinase 1 α (CK1 α).
Results: A model of Human CK1α bound to NS5A peptide with a conformation similar to that of the available crystal structure of protein kinase A – pseudo substrate complex has been generated using computational analysis and modelling. The consensus pattern for CK1α phosphorylation present in NS5A peptide is *SXXS , where the second S is the phosphorylation site of CK1α. Phosphorylation of serine2204 depends on the presence of phosphoserine (*S).
The structural basis of interaction between the kinase and the substrate is analyzed. The model generated showed Arginine 170 of CK1α being in proximal distance with phosphate group of phosphoserine which can make ionic interactions. Moreover, this Arginine residue is completely conserved among CK1 family. This clearly supports that Arginine 170 is the interacting residue with the phosphoserine (*S) of NS5A peptide of HCV.
Conclusion: Charge along with the substrate consensus pattern (*SXXS) plays a role in substrate recognition and binding to Human CK1alpha. Kinase inhibitors to prevent NS5A phosphorylation could severely affect the biological role of Human CK1alpha as it is involved in cell cycle control, apoptosis, Wnt signaling cascade for cell proliferation, differentiation and deregulation of CK1α expression has been linked to Alzheimer’s and Parkinson’s disease. Docking studies can be carried out using a small molecule to prevent interaction between NS5A peptide and Human CK1α which can serve as a potential drug candidate for HCV therapy.