3rrt
Structure of the RSV F protein in the post-fusion conformation
Structural highlights
FunctionFUS_HRSVA 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 plasma cell membrane fusion, the heptad repeat (HR) regions 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 plasma cell membranes. Directs fusion of viral and cellular membranes leading to delivery of the nucleocapsid into the cytoplasm. This fusion is pH independent and occurs directly at the outer cell membrane. The trimer of F1-F2 (protein F) interacts with glycoprotein G at the virion surface. Upon binding of G to heparan sulfate, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between host cell and virion membranes. Notably, RSV fusion protein is able to interact directly with heparan sulfate and therefore actively participates in virus attachment. Furthermore, the F2 subunit was identifed as the major determinant of RSV host cell specificity. Later in infection, proteins F expressed at the plasma membrane of infected cells mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis. The fusion protein is also able to trigger p53-dependent apoptosis.[1] [2] Publication Abstract from PubMedRespiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies such as 101F, palivizumab, and motavizumab, target two major antigenic sites on the RSV F glycoprotein. Structures of these sites as peptide complexes with motavizumab and 101F have been previously determined, but a structure of the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here we present the 2.8 A crystal structure of the trimeric RSV F ectodomain in its post-fusion conformation. The structure revealed that the 101F and motavizumab epitopes are present in the post-fusion state, and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the post-fusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and motavizumab can bind to multiple conformations of the fusion glycoprotein, and neutralize late in the fusion process. The structural preservation of neutralizing epitopes in the post-fusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen. Structure of the Respiratory Syncytial Virus Fusion Glycoprotein in the Post-fusion Conformation Reveals Preservation of Neutralizing Epitopes.,McLellan JS, Yang Y, Graham BS, Kwong PD J Virol. 2011 May 25. PMID:21613394[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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