Document Detail


Aromatic amino acids in the juxtamembrane domain of severe acute respiratory syndrome coronavirus spike glycoprotein are important for receptor-dependent virus entry and cell-cell fusion.
MedLine Citation:
PMID:  18199653     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The severe acute respiratory syndrome coronavirus (SARS-CoV) spike glycoprotein (S) is a class I viral fusion protein that binds to its receptor glycoprotein, human angiotensin converting enzyme 2 (hACE2), and mediates virus entry and cell-cell fusion. The juxtamembrane domain (JMD) of S is an aromatic amino acid-rich region proximal to the transmembrane domain that is highly conserved in all coronaviruses. Alanine substitutions for one or two of the six aromatic residues in the JMD did not alter the surface expression of the SARS-CoV S proteins with a deletion of the C-terminal 19 amino acids (S Delta19) or reduce binding to soluble human ACE2 (hACE2). However, hACE2-dependent entry of trypsin-treated retrovirus pseudotyped viruses expressing JMD mutant S Delta19 proteins was greatly reduced. Single alanine substitutions for aromatic residues reduced entry to 10 to 60% of the wild-type level. The greatest reduction was caused by residues nearest the transmembrane domain. Four double alanine substitutions reduced entry to 5 to 10% of the wild-type level. Rapid hACE2-dependent S-mediated cell-cell fusion was reduced to 60 to 70% of the wild-type level for all single alanine substitutions and the Y1188A/Y1191A protein. S Delta19 proteins with other double alanine substitutions reduced cell-cell fusion further, from 40% to less than 20% of wild-type levels. The aromatic amino acids in the JMD of the SARS-CoV S glycoprotein play critical roles in receptor-dependent virus-cell and cell-cell fusion. Because the JMD is so highly conserved in all coronavirus S proteins, it is a potential target for development of drugs that may inhibit virus entry and/or cell-cell fusion mediated by S proteins of all coronaviruses.
Authors:
Megan W Howard; Emily A Travanty; Scott A Jeffers; M K Smith; Sonia T Wennier; Larissa B Thackray; Kathryn V Holmes
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2008-01-16
Journal Detail:
Title:  Journal of virology     Volume:  82     ISSN:  1098-5514     ISO Abbreviation:  J. Virol.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-02-26     Completed Date:  2008-03-31     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0113724     Medline TA:  J Virol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2883-94     Citation Subset:  IM    
Affiliation:
Dept. of Microbiology, Mail Stop 8333, 12800 East 19th Ave, P.O. Box 6511, Aurora, CO 80045, USA.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Sequence
Amino Acids, Aromatic / chemistry,  physiology*
Base Sequence
Cell Fusion*
Cell Line
DNA Primers
Humans
Membrane Glycoproteins / chemistry,  physiology*
Membrane Proteins / chemistry,  physiology*
Molecular Sequence Data
Receptors, Virus / chemistry,  physiology*
SARS Virus / physiology*
Sequence Homology, Amino Acid
Viral Envelope Proteins / chemistry,  physiology*
Grant Support
ID/Acronym/Agency:
P01-AI 59576/AI/NIAID NIH HHS; P30 CA046934/CA/NCI NIH HHS; T32 AI 52066/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids, Aromatic; 0/DNA Primers; 0/Membrane Glycoproteins; 0/Membrane Proteins; 0/Receptors, Virus; 0/Viral Envelope Proteins; 107476-75-5/spike glycoprotein, coronavirus
Comments/Corrections

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