The structure of the fusion glycoprotein of Newcastle disease virus suggests a novel paradigm for the molecular mechanism of membrane fusion.
BACKGROUND
Membrane fusion within the Paramyxoviridae family of viruses is mediated by a surface glycoprotein termed the "F", or fusion, protein. Membrane fusion is assumed to involve a series of structural transitions of F from a metastable (prefusion) state to a highly stable (postfusion) state. No detail is available at the atomic level regarding the metastable form of these proteins or regarding the transitions accompanying fusion.


RESULTS
The three-dimensional structure of the fusion protein of Newcastle disease virus (NDV-F) has been determined. The trimeric NDV-F molecule is organized into head, neck, and stalk regions. The head is comprised of a highly twisted beta domain and an additional immunoglobulin-like beta domain. The neck is formed by the C-terminal extension of the heptad repeat region HR-A, capped by a four-helical bundle. The C terminus of HR-A is encased by a further helix HR-C and a 4-stranded beta sheet. The stalk is formed by the remaining visible portion of HR-A and by polypeptide immediately N-terminal to the C-terminal heptad repeat region HR-B. An axial channel extends through the head and neck and is fenestrated by three large radial channels located approximately at the head-neck interface.


CONCLUSIONS
We propose that prior to fusion activation, the hydrophobic fusion peptides in NDV-F are sequestered within the radial channels within the head, with the central HR-A coiled coil being only partly formed. Fusion activation then involves, inter alia, the assembly of a complete HR-A coiled coil, with the fusion peptides and transmembrane anchors being brought into close proximity. The structure of NDV-F is fundamentally different than that of influenza virus hemagglutinin, in that the central coiled coil is in the opposite orientation with respect to the viral membrane.
Chen
L
L
Biomolecular Research Institute, Parkville, Victoria 3052, Australia.
Gorman
J J
JJ
McKimm-Breschkin
J
J
Lawrence
L J
LJ
Tulloch
P A
PA
Smith
B J
BJ
Colman
P M
PM
Lawrence
M C
MC
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D009522:Newcastle disease virus / Q000737:chemistry*; D020836:Protein Structure, Quaternary; D016415:Sequence Alignment; D014760:Viral Fusion Proteins / Q000737:chemistry*
D014760:Viral Fusion Proteins