Document Detail

Specificity of human rhinovirus 2A(pro) is determined by combined spatial properties of four cleavage site residues.
MedLine Citation:
PMID:  23580429     Owner:  NLM     Status:  MEDLINE    
The 2A proteinase (2A(pro)) of human rhinoviruses cleaves the virally encoded polyprotein between the C terminus of VP1 and its own N terminus. Poor understanding of the 2A(pro) substrate specificity of this enzyme has hampered progress in developing inhibitors that may serve as antiviral agents. We show here that the 2A(pro) of human rhinovirus (HRV) 1A and 2 (rhinoviruses from genetic group A) cannot self-process at the HRV14 (a genetic group B rhinovirus) cleavage site. When the amino acids in the cleavage site of HRV2 2A(pro) (Ile-Ile-Thr-Thr-Ala*Gly-Pro-Ser-Asp) were singly or doubly replaced with the corresponding HRV14 residues (Asp-Ile-Lys-Ser-Tyr*Gly-Leu-Gly-Pro) at positions from P3 to P2', HRV1A and HRV2 2A(pro) cleavage took place at WT levels. However, when three or more positions of the HRV1A or 2 2A(pro) were substituted (e.g. at P2, P1 and P2'), cleavage in vitro was essentially eliminated. Introduction of the full HRV14 cleavage site into a full-length clone of the HRV1A and transfection of HeLa cells with a transcribed RNA did not give rise to viable virus. In contrast, revertant viruses bearing cysteine at the P1 position or proline at P2' were obtained when an RNA bearing the three inhibitory amino acids was transfected. Reversions in the enzyme affecting substrate specificity were not found in any of the in vivo experiments. Modelling of oligopeptide substrates onto the structure of HRV2 2A(pro) revealed no appreciable differences in residues of HRV2 and HRV14 in the respective substrate binding sites, suggesting that the overall shape of the substrate is important in determining binding efficiency.
David Neubauer; Martina Aumayr; Irene Gösler; Tim Skern
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2013-04-11
Journal Detail:
Title:  The Journal of general virology     Volume:  94     ISSN:  1465-2099     ISO Abbreviation:  J. Gen. Virol.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-19     Completed Date:  2013-08-23     Revised Date:  2014-01-30    
Medline Journal Info:
Nlm Unique ID:  0077340     Medline TA:  J Gen Virol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1535-46     Citation Subset:  IM    
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MeSH Terms
Amino Acid Sequence
Cysteine Endopeptidases / genetics,  metabolism*
HeLa Cells
Models, Molecular
Picornaviridae Infections / virology
Polyproteins / chemistry*,  metabolism
Rhinovirus / classification,  genetics
Substrate Specificity
Viral Proteins / chemistry*,  genetics,  metabolism
Grant Support
P 20889-B12//Austrian Science Fund FWF; P 24038-B20//Austrian Science Fund FWF
Reg. No./Substance:
0/Oligopeptides; 0/Polyproteins; 0/Viral Proteins; EC 3.4.22.-/Cysteine Endopeptidases; EC 2A, Picornavirus

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