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Journal of Virology, May 2009, p. 4670-4677, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02646-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Role of Conserved Histidine Residues in the Low-pH Dependence of the Semliki Forest Virus Fusion Protein{triangledown}

Zhao-ling Qin,1,2 Yan Zheng,1 and Margaret Kielian1*

Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Microbiology, the Second Military Medical University, Shanghai, People's Republic of China2

Received 23 December 2008/ Accepted 13 February 2009

A wide variety of enveloped viruses infects cells by taking advantage of the low pH in the endocytic pathway to trigger virus-membrane fusion. For alphaviruses such as Semliki Forest virus (SFV), acidic pH initiates a series of conformational changes in the heterodimeric virus envelope proteins E1 and E2. Low pH dissociates the E2/E1 dimer, releasing the membrane fusion protein E1. E1 inserts into the target membrane and refolds to a trimeric hairpin conformation, thus driving the fusion reaction. The means by which E1 senses and responds to low pH is unclear, and protonation of conserved E1 histidine residues has been proposed as a possible mechanism. We tested the role of four conserved histidines by mutagenesis of the wild-type (wt) SFV infectious clone to create virus mutants with E1 H3A, H125A, H331A, and H331A/H333A mutations. The H125A, H331A, and H331A/H333A mutants had growth properties similar to those of wt SFV and showed modest change or no change in the pH dependence of virus-membrane fusion. By contrast, the E1 H3A mutation produced impaired virus growth and a markedly more acidic pH requirement for virus-membrane fusion. The dissociation of the H3A heterodimer and the membrane insertion of the mutant E1 protein were comparable to those of the wt in efficiency and pH dependence. However, the formation of the H3A homotrimer required a much lower pH and showed reduced efficiency. Together, these results and the location of H3 suggest that this residue acts to regulate the low-pH-dependent refolding of E1 during membrane fusion.

* 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

{triangledown} Published ahead of print on 25 February 2009.

Journal of Virology, May 2009, p. 4670-4677, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02646-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Nelson, S., Poddar, S., Lin, T.-Y., Pierson, T. C. (2009). Protonation of Individual Histidine Residues Is Not Required for the pH-Dependent Entry of West Nile Virus: Evaluation of the "Histidine Switch" Hypothesis. J. Virol. 83: 12631-12635 [Abstract] [Full Text]  


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