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The structure of Vaccina virus H7 protein displays A Novel Phosphoinositide binding fold required for membrane biogenesis
Structural highlights
FunctionPG112_VACCW Contributes to the formation of crescents and immature virions (IV). Interacts with phosphatidylinositol-3-phosphate (PI3P) and phosphatidylinositol-4-phosphate (PI4P) lipids in order to form virion membranes. Mechanistically, mediates proper formation of OPG125-hexamers, and hence the honey comb lattice and spherical immature virus (PubMed:35906465).[1] [2] [3] Publication Abstract from PubMedPhosphoinositides and phosphoinositide-binding proteins play a critical role in membrane and protein trafficking in eukaryotes. Their critical role in replication of cytoplasmic viruses has just begun to be understood. Poxviruses, a family of large cytoplasmic DNA viruses, rely on the intracellular membranes for developing their envelope, and poxvirus morphogenesis requires enzymes from the cellular phosphoinositide metabolic pathway. However, the role of phosphoinositides in poxvirus replication remains unclear, and no poxvirus proteins show any homology to eukaryotic phosphoinositide-binding domains. Recently, a group of poxvirus proteins, termed viral-membrane assembly proteins (VMAPs), were identified as essential for poxvirus membrane biogenesis. A key component of VMAPs is the H7 protein. Here, we report the crystal structure of the H7 protein from vaccinia virus. The H7 structure displays a novel fold comprised of seven alpha-helices and a highly curved three-stranded antiparallel beta-sheet. We identified a phosphoinositide-binding site in H7, comprised of basic residues on a surface patch and the flexible C-terminal tail. These residues were found to be essential for the viral replication and for the binding of H7 to phosphatidylinositol-3-phosphate (PI3P) and phosphatidylinositol-4-phosphate (PI4P). Our studies suggested that phosphoinositide binding by H7 plays an essential role in poxvirus membrane biogenesis. IMPORTANCE: Poxvirus viral membrane assembly proteins (VMAPs) were recently shown to be essential for poxvirus membrane biogenesis. One of the key components of VMAPs is the H7 protein. However, no known structural motifs could be identified from its sequence, and there are no homologs of H7 outside of the poxvirus family to suggest a biochemical function. We have determined the crystal structure of vaccinia virus H7 protein. The structure displays a novel fold with a distinct and positively charged surface. Our data demonstrate that H7 binds phosphatidylinositol-3-phosphate and phosphatidylinositol-4-phosphate, and the basic surface patch was indeed required for phosphoinositide binding. In addition, mutation of positively charged residues required for lipid binding disrupted VACV replication. Phosphoinositides and phosphoinositide-binding proteins play critical roles in membrane and protein trafficking in eukaryotes. Our study demonstrates that VACV H7 displays a novel fold for phosphoinositide binding, which is essential for poxvirus replication. Structure-function Analysis of Vaccinia Virus H7 protein Reveals a Novel Phosphoinositide Binding Fold Essential for Poxvirus Replication.,Kolli S, Meng X, Wu X, Shengjuler D, Cameron CE, Xiang Y, Deng J J Virol. 2014 Dec 3. pii: JVI.03073-14. PMID:25473060[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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