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Journal of Virology, November 2008, p. 11398-11409, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.02654-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Residues in the Stalk Domain of the Hendra Virus G Glycoprotein Modulate Conformational Changes Associated with Receptor Binding{triangledown}

Kimberly A. Bishop,1,{dagger} Andrew C. Hickey,1 Dimple Khetawat,1 Jared R. Patch,1 Katharine N. Bossart,2 Zhongyu Zhu,3,4 Lin-Fa Wang,2 Dimiter S. Dimitrov,3 and Christopher C. Broder1*

Department of Microbiology and Immunology, Uniformed Services University, Bethesda, Maryland 20814,1 CSIRO Livestock Industries, Australian Animal Health Laboratory, Geelong, Victoria 3220, Australia,2 Protein Interactions Group, CCRNP, CCR, NCI-Frederick, NIH, Frederick, Maryland 21702,3 BRP, SAIC-Frederick, Inc., NCI-Frederick, Frederick, Maryland 217024

Received 13 December 2007/ Accepted 22 August 2008

Hendra virus (HeV) is a member of the broadly tropic and highly pathogenic paramyxovirus genus Henipavirus. HeV is enveloped and infects cells by using membrane-anchored attachment (G) and fusion (F) glycoproteins. G possesses an N-terminal cytoplasmic tail, an external membrane-proximal stalk domain, and a C-terminal globular head that binds the recently identified receptors ephrinB2 and ephrinB3. Receptor binding is presumed to induce conformational changes in G that subsequently trigger F-mediated fusion. The stalk domains of other attachment glycoproteins appear important for oligomerization and F interaction and specificity. However, this region of G has not been functionally characterized. Here we performed a mutagenesis analysis of the HeV G stalk, targeting a series of isoleucine residues within a hydrophobic {alpha}-helical domain that is well conserved across several attachment glycoproteins. Nine of 12 individual HeV G alanine substitution mutants possessed a complete defect in fusion-promotion activity yet were cell surface expressed and recognized by a panel of conformation-dependent monoclonal antibodies (MAbs) and maintained their oligomeric structure. Interestingly, these G mutations also resulted in the appearance of an additional electrophoretic species corresponding to a slightly altered glycosylated form. Analysis revealed that these G mutants appeared to adopt a receptor-bound conformation in the absence of receptor, as measured with a panel of MAbs that preferentially recognize G in a receptor-bound state. Further, this phenotype also correlated with an inability to associate with F and in triggering fusion even after receptor engagement. Together, these data suggest the stalk domain of G plays an important role in the conformational stability and receptor binding-triggered changes leading to productive fusion, such as the dissociation of G and F.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD 20814. Phone: (301) 295-3401. Fax: (301) 295-1545. E-mail: cbroder{at}usuhs.mil

{triangledown} Published ahead of print on 17 September 2008.

{dagger} Present address: Biological Defense Research Directorate Annex, Naval Medical Research Center, Rockville, MD 20852.

Journal of Virology, November 2008, p. 11398-11409, Vol. 82, No. 22
0022-538X/08/$08.00+0     doi:10.1128/JVI.02654-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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