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  • Review Article
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The structural biology of type I viral membrane fusion

Nature Reviews Molecular Cell Biology volume 4, pages 309–319 (2003)Cite this article

Key Points

  • Fusion proteins, which are viral envelope glycoproteins, participate actively in fusing viral and target-cell membranes.

  • Fusion proteins are thought to adopt a metastable conformation that relaxes to a highly stable conformation during the membrane-fusion event. This highly stable structure has been characterized for several viruses and has shown that there is a common structural motif.

  • For influenza viruses, and now also for paramyxoviruses, structural information is available for the metastable form, and this information indicates the nature of the protein conformational changes that accompany membrane fusion.

  • Although influenza viruses trigger fusion inside endosomes, for many viruses the fusion event occurs at the plasma membrane of the target cell and, in these cases, extra proteins in the viral envelope might be involved in assisting the fusion process.

  • For human immunodeficiency virus (HIV), large conformational changes in the glycoprotein gp120 accompany receptor binding and these changes might be involved in priming the fusion protein gp41.

  • An increased understanding of the structural pathways that connect the metastable and highly stable conformers of the fusion protein is helping us to discover candidate drugs that block viral entry into cells.

Abstract

The fusion of viral membranes with target-cell membranes is an essential step in the entry of enveloped viruses into cells, and recent X-ray structures of paramyxoviral envelope proteins have provided new insights into protein-mediated plasma-membrane fusion. Here, we review our understanding of the structural transitions that are involved in this fusion pathway, compare it to our understanding of influenza virus membrane fusion, and discuss the implications for retroviral membrane fusion.

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Figure 1: A model pathway of type I viral membrane fusion.
Figure 2: Three structures of the influenza virus haemagglutinin.
Figure 3: The double-layered helical rod structure of type I viral fusion proteins.
Figure 4: Experimental and proposed structures of the paramyxovirus fusion protein.
Figure 5: Electrostatic potential on the surface of the radial and axial channels of Newcastle disease virus F0′ protein.
Figure 6: A schematic of the experimental and proposed structures of HIV gp41.

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Acknowledgements

All of the molecular graphics in this review were produced using combinations of MOLSCRIPT71, RASTER3D72 and GRASP73. P.M.C. would like to thank the National Health and Medical Research Council (Australia) and the Cancer Council Victoria for their support.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Peter M. Colman

  2. Commonwealth Scientific & Industrial Research Organisation, Health Science and Nutrition, 343 Royal Parade, Parkville, 3052, Victoria, Australia

    Michael C. Lawrence

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DATABASES

Swiss-Prot

E

F

gp160

HA

HN

FURTHER INFORMATION

The Walter and Eliza Hall Institute of Medical Research

Commonwealth Scientific & Industrial Research Organisation

Glossary

VIRAL FUSION PROTEIN

A glycoprotein that is anchored to the viral envelope. Its extracellular domain causes the fusion of the viral membrane with a membrane of target cells.

METASTABLE STATE

A state that is marginally stable (in the case of fusion proteins, by virtue of the existence of a 'nearby' stable state that is separated from it by an energy barrier).

HR-A AND HR-B

Heptad repeats or helical regions A and B of viral fusion proteins, which associate with one another in the post-fusion conformation.

COILED-COILS

Two or more helical segments of polypeptide that align either parallel or anti-parallel to each other and then twist around one another in a rope-like fashion. Such an arrangement can often be predicted from amino-acid sequence analysis.

PARAMYXOVIRUSES

The Paramyxoviridae family has two subfamilies — Paramyxovirinae (which includes parainfluenza viruses, mumps virus and measles virus) and Pneumovirinae (which includes respiratory syncytial virus). Members of both subfamilies have a related fusion protein.

N-PEPTIDES AND C-PEPTIDES

Peptides that are derived from heptad repeat or helical region (HR)-A and HR-B of viral fusion proteins, respectively.

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Colman, P., Lawrence, M. The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 4, 309–319 (2003). https://doi.org/10.1038/nrm1076

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