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Journal of Virology, May 2009, p. 4121-4126, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02410-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Intersubunit Interactions Modulate pH-Induced Activation of Membrane Fusion by the Junín Virus Envelope Glycoprotein GPC{triangledown}

Joanne York and Jack H. Nunberg*

Montana Biotechnology Center, The University of Montana, Missoula, Montana 59812

Received 21 November 2008/ Accepted 3 February 2009

The mature arenavirus envelope glycoprotein GPC is a tripartite complex comprising a stable signal peptide (SSP) in addition to the receptor-binding (G1) and transmembrane fusion (G2) subunits. We have shown previously that SSP is a key element in GPC-mediated membrane fusion, and that GPC sensitivity to acidic pH is modulated in part through the lysine residue at position 33 in the ectodomain loop of SSP (J. York and J. H. Nunberg, J. Virol. 80:7775-7780, 2006). A glutamine substitution at this position stabilizes the native GPC complex and thereby prevents the induction of pH-dependent membrane fusion. In efforts to identify the intersubunit interactions of K33, we performed alanine-scanning mutagenesis at charged residues in the membrane-proximal ectodomain of G2 and determined the ability of these mutations to rescue the fusion deficiency in K33Q GPC. Four second-site mutations that specifically complement K33Q were identified (D400A, E410A, R414A, and K417A). Moreover, complementation was also observed at three hydrophobic positions in the membrane-spanning domain of G2 (F427, W428, and F438). Interestingly, all of the complementing mutations restored wild-type pH sensitivity to the K33Q mutant, while none themselves affected the pH of membrane fusion. Our studies demonstrate a specific interaction between SSP and G2 that is involved in priming the native GPC complex for pH-induced membrane fusion. Importantly, this pH-dependent interaction has been shown to be vulnerable to small-molecule compounds that stabilize the native complex and prevent the activation of membrane fusion. A detailed mechanistic understanding of the control of GPC-mediated membrane fusion will be important in guiding the development of effective therapeutics against arenaviral hemorrhagic fever.

* Corresponding author. Mailing address: Montana Biotechnology Center, The University of Montana, Science Complex, Room 221, Missoula, MT 59812. Phone: (406) 243-6421. Fax: (406) 243-6425. E-mail: jack.nunberg{at}umontana.edu

{triangledown} Published ahead of print on 18 February 2009.

Journal of Virology, May 2009, p. 4121-4126, Vol. 83, No. 9
0022-538X/09/$08.00+0     doi:10.1128/JVI.02410-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Agnihothram, S. S., Dancho, B., Grant, K. W., Grimes, M. L., Lyles, D. S., Nunberg, J. H. (2009). Assembly of Arenavirus Envelope Glycoprotein GPC in Detergent-Soluble Membrane Microdomains. J. Virol. 83: 9890-9900 [Abstract] [Full Text]  


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