文章基本信息

标题：Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus
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作者：Benhur Lee ; Olivier Pernet ; Asim A. Ahmed 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：17
页码：E2156-E2165
DOI：10.1073/pnas.1501690112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceAfrican henipaviruses (HNVs) may be responsible for the misdiagnosis of encephalitis-associated outbreaks of malaria. Host-cell infection by an African HNV relies on the initial interaction between a virally encoded surface glycoprotein and a host-cell receptor. Here, we provide a structural description of how a bat-borne Ghanaian HNV hijacks human ephrinB2 to facilitate cross-species transmission. We demonstrate that, although the Ghanian HNV is sequence dissimilar (<30% sequence identity) and displays a receptor-binding scaffold that differs significantly in structure to pathogenic HNV relatives from Asia, it adopts a nearly identical primary ephrinB2 binding mode. These data provide a molecular-level explanation for previously observed spillover of African HNVs into human populations. The discovery of African henipaviruses (HNVs) related to pathogenic Hendra virus (HeV) and Nipah virus (NiV) from Southeast Asia and Australia presents an open-ended health risk. Cell receptor use by emerging African HNVs at the stage of host-cell entry is a key parameter when considering the potential for spillover and infection of human populations. The attachment glycoprotein from a Ghanaian bat isolate (GhV-G) exhibits <30% sequence identity with Asiatic NiV-G/HeV-G. Here, through functional and structural analysis of GhV-G, we show how this African HNV targets the same human cell-surface receptor (ephrinB2) as the Asiatic HNVs. We first characterized this virus-receptor interaction crystallographically. Compared with extant HNV-G-ephrinB2 structures, there was significant structural variation in the six-bladed {beta}-propeller scaffold of the GhV-G receptor-binding domain, but not the Greek key fold of the bound ephrinB2. Analysis revealed a surprisingly conserved mode of ephrinB2 interaction that reflects an ongoing evolutionary constraint among geographically distal and phylogenetically divergent HNVs to maintain the functionality of ephrinB2 recognition during virus-host entry. Interestingly, unlike NiV-G/HeV-G, we could not detect binding of GhV-G to ephrinB3. Comparative structure-function analysis further revealed several distinguishing features of HNV-G function: a secondary ephrinB2 interaction site that contributes to more efficient ephrinB2-mediated entry in NiV-G relative to GhV-G and cognate residues at the very C terminus of GhV-G (absent in Asiatic HNV-Gs) that are vital for efficient receptor-induced fusion, but not receptor binding per se. These data provide molecular-level details for evaluating the likelihood of African HNVs to spill over into human populations.
关键词：emerging virus ; viral attachment ; glycoprotein ; henipavirus ; structure