Crystal structure of the marburg virus GP2 core domain in its postfusion conformation

Jayne F. Koellhoffer, Vladimir N. Malashkevich, Joseph S. Harrison, Rafael Toro, Rahul C. Bhosle, Kartik Chandran, Steven C. Almo, Jonathan R. Lai

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Marburg virus (MARV) and Ebola virus (EBOV) are members of the family Filoviridae ("filoviruses") and cause severe hemorrhagic fever with human case fatality rates of up to 90%. Filovirus infection requires fusion of the host cell and virus membranes, a process that is mediated by the envelope glycoprotein (GP). GP contains two subunits, the surface subunit (GP1), which is responsible for cell attachment, and the transmembrane subunit (GP2), which catalyzes membrane fusion. The GP2 ectodomain contains two heptad repeat regions, N-terminal and C-terminal (NHR and CHR, respectively), that adopt a six-helix bundle during the fusion process. The refolding of this six-helix bundle provides the thermodynamic driving force to overcome barriers associated with membrane fusion. Here we report the crystal structure of the MARV GP2 core domain in its postfusion (six-helix bundle) conformation at 1.9 Å resolution. The MARV GP2 core domain backbone conformation is virtually identical to that of EBOV GP2 (reported previously), and consists of a central NHR core trimeric coiled coil packed against peripheral CHR α-helices and an intervening loop and helix-turn-helix segments. We previously reported that the stability of the MARV GP2 postfusion structure is highly pH-dependent, with increasing stability at lower pH [Harrison, J. S., Koellhoffer, J. K., Chandran, K., and Lai, J. R. (2012) Biochemistry51, 2515-2525]. We hypothesized that this pH-dependent stability provides a mechanism for conformational control such that the postfusion six-helix bundle is promoted in the environments of appropriately mature endosomes. In this report, a structural rationale for this pH-dependent stability is described and involves a high-density array of core and surface acidic side chains at the midsection of the structure, termed the "anion stripe". In addition, many surface-exposed salt bridges likely contribute to the stabilization of the postfusion structure at low pH. These results provide structural insights into the mechanism of MARV GP2-mediated membrane fusion.

Original languageEnglish (US)
Pages (from-to)7665-7675
Number of pages11
JournalBiochemistry
Volume51
Issue number39
DOIs
StatePublished - Oct 2 2012

ASJC Scopus subject areas

  • Biochemistry

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