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J. Virol. doi:10.1128/JVI.00366-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A CONSERVED REGION IN THE F₂ SUBUNIT OF PARAMYXOVIRUS FUSION PROTEINS IS INVOLVED IN FUSION REGULATION

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

^* To whom correspondence should be addressed. Email: rdutc2{at}uky.edu.

	Abstract

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, Gardner et al, 2007, Biochemistry 46:5094-105) and one in the F₂ subunit (CBF₂). To analyze the functions of CBF₂, alanine substitutions at conserved positions were created in both the 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 mutants Y79A and P89A showed significantly decreased levels of fusion, whereas the SV5 CBF₂ mutant I49A exhibited greatly increased cell-cell fusion relative to wild-type F. Additional substitutions at SV5 F I49 suggest that both side-chain volume and hydrophobicity at this position are important in folding of the metastable, prefusion state and subsequent triggering of membrane fusion. The recently published, prefusogenic structure of PIV5/SV5 F (Yin et al. 2006. Nature 439 :38-44) 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 of membrane fusion.

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