4g2k
Crystal structure of the Marburg Virus GP2 ectodomain in its post-fusion conformationCrystal structure of the Marburg Virus GP2 ectodomain in its post-fusion conformation
Structural highlights
FunctionVGP_MABVP GP1 is responsible for binding to the receptor(s) on target cells. Interacts with CD209/DC-SIGN and CLEC4M/DC-SIGNR which act as cofactors for virus entry into the host cell. Binding to CD209 and CLEC4M, which are respectively found on dendritic cells (DCs), and on endothelial cells of liver sinusoids and lymph node sinuses, facilitate infection of macrophages and endothelial cells. These interactions not only facilitate virus cell entry, but also allow capture of viral particles by DCs and subsequent transmission to susceptible cells without DCs infection (trans infection) (By similarity). GP2 acts as a class I viral fusion protein. Under the current model, the protein has at least 3 conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes. Responsible for penetration of the virus into the cell cytoplasm by mediating the fusion of the membrane of the endocytosed virus particle with the endosomal membrane. Low pH in endosomes induces an irreversible conformational change in GP2, releasing the fusion hydrophobic peptide (By similarity).GCN4_YEAST Is a transcription factor that is responsible for the activation of more than 30 genes required for amino acid or for purine biosynthesis in response to amino acid or purine starvation. Binds and recognize the DNA sequence: 5'-TGA[CG]TCA-3'. Publication Abstract from PubMedMarburg virus (MARV) and Ebola virus (EBOV) are members of the family Filoviridae ('filoviruses') that 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 post-fusion (six-helix bundle) conformation at 1.9 A 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 alpha-helices and an intervening loop/helix-turn-helix segment. We previously reported that the stability of the MARV GP2 post-fusion structure is highly pH-dependent, with increasing stability at lower pH [Harrison, J.S.; Koellhoffer, J. K.; Chandran, K.; and Lai, J. R. Biochemistry, 2012, 51, 2515-2525]. We hypothesized that this pH-dependent stability provides a mechanism for conformational control such that the post-fusion six helix bundle is promoted in the environments of appropriately matured 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 stabilizing the post-fusion structure at low pH. These results provide structural insights into the mechanism of MARV GP2-mediated membrane fusion. Crystal Structure of the Marburg Virus GP2 Core Domain in its Post-Fusion Conformation.,Koellhoffer JF, Malashkevich VN, Harrison JS, Toro R, Bhosle RC, Chandran K, Almo SC, Lai JR Biochemistry. 2012 Aug 30. PMID:22935026[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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