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Measles Virus Fusion Glycoprotein Postfusion Core (G464W Variant)
Structural highlights
FunctionFUS_MEASZ 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. During viral entry or virus-mediated fusion between infected cells and neighboring susceptible cells, the head domain of the H protein initially binds to its receptor and then the stalk region of the H protein transmits the fusion-triggering signal to the F protein (By similarity). Upon HN binding to its cellular receptor, the hydrophobic fusion peptide is unmasked and interacts with the cellular membrane, inducing the fusion between cell and virion membranes. Later in infection, F proteins expressed at the plasma membrane of infected cells could mediate fusion with adjacent cells to form syncytia, a cytopathic effect that could lead to tissue necrosis (By similarity).[UniProtKB:Q786F3] Some hyperfusogenic isolates can induce membrane fusion in SLAM- and nectin-4-negative cells and are linked to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE). The neuropathogenicity is closely associated with enhanced propagation mediated by cell-to-cell fusion in the brain, which is principally regulated by hyperfusogenic mutations of the viral F protein. Cell-to-cell transmission of the virus also occurs with hyperfusogenic isolates.[UniProtKB:Q786F3] Publication Abstract from PubMedFusion of the host membrane and viral envelope by class I viral fusion proteins is driven by the assembly of a postfusion six-helix bundle formed through antiparallel interactions between N-terminal (HR1) and C-terminal (HR2) heptad-repeat regions. Although mutations in these regions of the measles virus (MeV) fusion (F) glycoprotein are known to promote neuropathogenic and hyperfusogenic phenotypes, their effects on postfusion core stability have not been systematically examined. Here, we combine peptide biophysics and X-ray crystallography to interrogate how mutations within the HR2 domain, present in native neuropathogenic MeV isolates (e.g., L454W and N462K) and laboratory-generated hyperfusogenic variants (e.g., L454M and T461A), influence postfusion 6HB assembly. Circular dichroism (CD) spectroscopy reveals that, with few exceptions, these mutations decrease postfusion core stability, despite their association with enhanced fusion activity. We also report the first crystal structure of the wild-type MeV postfusion core as well as structures of six hyperfusogenic variants, enabling high-resolution comparison of the molecular basis of destabilization. Structural analysis shows that these effects arise from localized perturbations to steric packing, hydrogen bonding networks, and helix-stabilizing interactions within HR2, while the overall 6HB architecture remains conserved. Together, these results indicate that hyperfusogenic mutations are not associated with stabilization of the postfusion state and are instead consistent with models in which hyperfusogenicity arises from a reduction in the energetic barrier to fusion, potentially through effects on prefusion stability or triggering efficiency. These findings establish key sequence-structure-stability relationships governing coiled-coil assembly and provide a framework for the design of HR1- and HR2-based fusion inhibitors. Hyperfusogenic Mutations Destabilize the Postfusion Six-Helix Bundle of the Measles Virus Fusion Glycoprotein.,Vithanage N, Outlaw VK Biochemistry. 2026 Aug 4;65(15):2350-2358. doi: 10.1021/acs.biochem.6c00182. PMID:42485314[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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