4G2K

Crystal structure of the Marburg Virus GP2 ectodomain in its post-fusion conformation

Summary for 4G2K

• Entry DOI: 10.2210/pdb4g2k/pdb
• Descriptor: General control protein GCN4, Envelope glycoprotein GP2 chimera, GLYCEROL, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: gp2-gcn4 fusion, viral protein
• Biological source: Saccharomyces cerevisiae (yeast, Marburg virus); More
• Cellular location: GP2: Virion membrane ; Single-pass type I membrane protein . GP1: Virion membrane ; Peripheral membrane protein : P35254
• Total number of polymer chains: 3
• Total formula weight: 44295.34

Authors

Malashkevich, V.N.,Koellhoffer, J.F.,Harrison, J.S.,Toro, R.,Bhosle, R.C.,Chandran, K.,Lai, J.R.,Almo, S.C. (deposition date: 2012-07-12, release date: 2012-09-12, Last modification date: 2024-11-27)

Primary citation

Koellhoffer, J.F.,Malashkevich, V.N.,Harrison, J.S.,Toro, R.,Bhosle, R.C.,Chandran, K.,Almo, S.C.,Lai, J.R.
Crystal Structure of the Marburg Virus GP2 Core Domain in Its Postfusion Conformation.
Biochemistry, 51:7665-7675, 2012

PubMed 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.

PubMed: 22935026
DOI: 10.1021/bi300976m

Experimental method

X-RAY DIFFRACTION (1.9 Å)