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Journal of Virology, August 2007, p. 8303-8314, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00366-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Conserved Region in the F2 Subunit of Paramyxovirus Fusion Proteins Is Involved In Fusion Regulation{triangledown}

Amanda E. Gardner and Rebecca E. Dutch*

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509

Received 20 February 2007/ Accepted 8 May 2007

Paramyxoviruses utilize both an attachment protein and a fusion (F) protein to drive virus-cell and cell-cell fusion. F exists functionally as a trimer of two disulfide-linked subunits: F1 and F2. Alignment and analysis of a set of paramyxovirus F protein sequences identified three conserved blocks (CB): one in the fusion peptide/heptad repeat A domain, known to play important roles in fusion promotion, one in the region between the heptad repeats of F1 (CBF1) (A. E. Gardner, K. L. Martin, and R. E. Dutch, Biochemistry 46:5094-5105, 2007), and one in the F2 subunit (CBF2). To analyze the functions of CBF2, alanine substitutions at conserved positions were created in both the simian virus 5 (SV5) and Hendra virus F proteins. A number of the CBF2 mutations resulted in folding and expression defects. However, the CBF2 mutants that were properly expressed and trafficked had altered fusion promotion activity. The Hendra virus CBF2 Y79A and P89A mutants showed significantly decreased levels of fusion, whereas the SV5 CBF2 I49A mutant exhibited greatly increased cell-cell fusion relative to that for wild-type F. Additional substitutions at SV5 F I49 suggest that both side chain volume and hydrophobicity at this position are important in the folding of the metastable, prefusion state and the subsequent triggering of membrane fusion. The recently published prefusogenic structure of parainfluenza virus 5/SV5 F (H. S. Yin et al., Nature 439:38-44, 2006) places CBF2 in direct contact with heptad repeat A. Our data therefore indicate that this conserved region plays a critical role in stabilizing the prefusion state, likely through interactions with heptad repeat A, and in triggering membrane fusion.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Biomedical Biological Sciences Research Building, 741 S. Limestone, Lexington, KY 40536-0509. Phone: (859) 323-1795. Fax: (859) 323-1037. E-mail: rdutc2{at}uky.edu

{triangledown} Published ahead of print on 16 May 2007.

Journal of Virology, August 2007, p. 8303-8314, Vol. 81, No. 15
0022-538X/07/$08.00+0     doi:10.1128/JVI.00366-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Whitman, S. D., Smith, E. C., Dutch, R. E. (2009). Differential Rates of Protein Folding and Cellular Trafficking for the Hendra Virus F and G Proteins: Implications for F-G Complex Formation. J. Virol. 83: 8998-9001 [Abstract] [Full Text]  
  • Schowalter, R. M., Chang, A., Robach, J. G., Buchholz, U. J., Dutch, R. E. (2009). Low-pH Triggering of Human Metapneumovirus Fusion: Essential Residues and Importance in Entry. J. Virol. 83: 1511-1522 [Abstract] [Full Text]  
  • Long, G., Pan, X., Vlak, J. M. (2008). Conserved Leucines in N-Terminal Heptad Repeat HR1 of Envelope Fusion Protein F of Group II Nucleopolyhedroviruses Are Important for Correct Processing and Essential for Fusogenicity. J. Virol. 82: 2437-2447 [Abstract] [Full Text]  


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