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Journal of Virology, April 2004, p. 3312-3318, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3312-3318.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Multistep Regulation of Membrane Insertion of the Fusion Peptide of Semliki Forest Virus

Don L. Gibbons,1,{dagger} Anna Ahn,1,{dagger},{ddagger} Maofu Liao,1 Lena Hammar,2 R. Holland Cheng,2 and Margaret Kielian1*

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Biosciences, Karolinska Institute, S-141 57 Huddinge, Sweden2

Received 2 September 2003/ Accepted 3 December 2003

A prevailing model for virus membrane fusion proteins has been that the hydrophobic fusion peptide is hidden in the prefusion conformation, becomes exposed once the fusion reaction is triggered, and then either inserts into target membranes or is rapidly inactivated. This model is in general agreement with the structure and mechanism of class I fusion proteins, such as the influenza virus hemagglutinin. We here describe studies of the class II fusion protein E1 from the alphavirus Semliki Forest virus (SFV). SFV fusion is triggered by low pH, which releases E1 from its heterodimeric interaction with the E2 protein and induces the formation of a stable E1 homotrimer. The exposure and target membrane interaction of the E1 fusion peptide (residues 83 to 100) were followed using a monoclonal antibody (MAb E1f) mapping to E1 residues 85 to 95. In agreement with the known structure of SFV and other alphaviruses, the fusion peptide was shielded in native SFV particles and exposed when E1-E2 dimer dissociation was triggered by acidic pH. In contrast, the fusion peptide on purified E1 ectodomains (E1*) was fully accessible at neutral pH. Functional assays showed that MAb E1f binding at neutral pH prevented subsequent low-pH-triggered E1* interaction with target membranes and trimerization. E1* was not inactivated by low pH when treated either in the absence of target membranes or in the presence of fusion-inactive cholesterol-deficient liposomes. Thus, the membrane insertion of the E1 fusion peptide is regulated by additional low-pH-dependent steps after exposure, perhaps involving an E1-cholesterol interaction.

* Corresponding author. Mailing address: Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3638. Fax: (718) 430-8574. E-mail: kielian{at}aecom.yu.edu.

{dagger} D.L.G. and A.A. contributed equally to this work.

{ddagger} Present address: New York Medical College, Valhalla, N.Y.

Journal of Virology, April 2004, p. 3312-3318, Vol. 78, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.7.3312-3318.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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