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Journal of Virology, July 2008, p. 6337-6348, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02576-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Length Requirements for Membrane Fusion of Influenza Virus Hemagglutinin Peptide Linkers to Transmembrane or Fusion Peptide Domains {triangledown}

Zhu-Nan Li,1 Byeong-Jae Lee,1 William A. Langley,1 Konrad C. Bradley,1 Rupert J. Russell,2 and David A. Steinhauer1*

Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322,1 Interdisciplinary Center for Avian and Human Influenza Research, School of Biology, University of St. Andrews, Fife KY16 9ST, United Kingdom2

Received 3 December 2007/ Accepted 5 April 2008

During membrane fusion, the influenza A virus hemagglutinin (HA) adopts an extended helical structure that contains the viral transmembrane and fusion peptide domains at the same end of the molecule. The peptide segments that link the end of this rod-like structure to the membrane-associating domains are approximately 10 amino acids in each case, and their structure at the pH of fusion is currently unknown. Here, we examine mutant HAs and influenza viruses containing such HAs to determine whether these peptide linkers are subject to specific length requirements for the proper folding of native HA and for membrane fusion function. Using pairwise deletions and insertions, we show that the region flanking the fusion peptide appears to be important for the folding of the native HA structure but that mutant proteins with small insertions can be expressed on the cell surface and are functional for membrane fusion. HA mutants with deletions of up to 10 residues and insertions of as many as 12 amino acids were generated for the peptide linker to the viral transmembrane domain, and all folded properly and were expressed on the cell surface. For these mutants, it was possible to designate length restrictions for efficient membrane fusion, as functional activity was observed only for mutants containing linkers with insertions or deletions of eight residues or less. The linker peptide mutants are discussed with respect to requirements for the folding of native HAs and length restrictions for membrane fusion activity.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. Phone: (404) 712-8542. Fax: (404) 727-3659. E-mail: steinhauer{at}microbio.emory.edu

{triangledown} Published ahead of print on 16 April 2008.

Journal of Virology, July 2008, p. 6337-6348, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02576-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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