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    Mutations in the fusion peptide and adjacent heptad repeat inhibit folding or activity of the Newcastle disease virus fusion protein

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    Authors
    Sergel, Theresa A.
    McGinnes, Lori
    Morrison, Trudy G.
    UMass Chan Affiliations
    Department of Molecular Genetics and Microbiology
    Document Type
    Journal Article
    Publication Date
    2001-08-03
    Keywords
    Amino Acid Sequence
    Animals
    COS Cells
    Centrifugation, Density Gradient
    Cercopithecus aethiops
    Flow Cytometry
    Fluorescent Antibody Technique
    Molecular Sequence Data
    *Mutation
    Newcastle disease virus
    Peptides
    *Protein Folding
    Viral Fusion Proteins
    Life Sciences
    Medicine and Health Sciences
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    Abstract
    Paramyxovirus fusion proteins have two heptad repeat domains, HR1 and HR2, which have been implicated in the fusion activity of the protein. Peptides with sequences from these two domains form a six-stranded coiled coil, with the HR1 sequences forming a central trimer (K. A. Baker, R. E. Dutch, R. A. Lamb, and T. S. Jardetzky, Mol. Cell 3:309-319, 1999; X. Zhao, M. Singh, V. N. Malashkevich, and P. S. Kim, Proc. Natl. Acad. Sci. USA 97:14172-14177, 2000). We have extended our previous mutational analysis of the HR1 domain of the Newcastle disease virus fusion protein, focusing on the role of the amino acids forming the hydrophobic core of the trimer, amino acids in the "a" and "d" positions of the helix from amino acids 123 to 182. Both conservative and nonconservative point mutations were characterized for their effects on synthesis, stability, proteolytic cleavage, and surface expression. Mutant proteins expressed on the cell surface were characterized for fusion activity by measuring syncytium formation, content mixing, and lipid mixing. We found that all mutations in the "a" position interfered with proteolytic cleavage and surface expression of the protein, implicating the HR1 domain in the folding of the F protein. However, mutation of five of seven "d" position residues had little or no effect on surface expression but, with one exception at residue 175, did interfere to various extents with the fusion activity of the protein. One of these "d" mutations, at position 154, interfered with proteolytic cleavage, while the rest of the mutants were cleaved normally. That most "d" position residues do affect fusion activity argues that a stable HR1 trimer is required for formation of the six-stranded coiled coil and, therefore, optimal fusion activity. That most of the "d" position mutations do not block folding suggests that formation of the core trimer may not be required for folding of the prefusion form of the protein. We also found that mutations within the fusion peptide, at residue 128, can interfere with folding of the protein, implicating this region in folding of the molecule. No characterized mutation enhanced fusion.
    Source
    J Virol. 2001 Sep;75(17):7934-43.
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/38676
    PubMed ID
    11483738
    Related Resources
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    UMass Chan Faculty and Researcher Publications

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