Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus
Molecular recognition of human ephrinB2 cell surface receptor by an emergent African henipavirus
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DOI：
10.1073/pnas.1501690112
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发表时间：
2015-03
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影响因子：
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通讯作者：
Benhur Lee;O. Pernet;Asim A. Ahmed;A. Zeltiña;S. Beaty;T. Bowden
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作者：
Benhur Lee;O. Pernet;Asim A. Ahmed;A. Zeltiña;S. Beaty;T. Bowden
非洲亨尼帕病毒（HNVs）可能是导致脑炎相关疟疾暴发误诊的原因。非洲HNV的宿主细胞感染依赖于病毒编码的表面糖蛋白和宿主细胞受体之间的初始相互作用。在这里，我们提供了一个蝙蝠传播的加纳HNV劫持人类ephrinB 2，以促进跨物种传播的结构描述。我们证明，虽然加纳HNV是序列不相似的（<30%的序列同一性），并显示受体结合支架，在结构上显着不同的致病性HNV亲属从亚洲，它采用了几乎相同的初级ephrinB 2结合模式。这些数据为先前观察到的非洲HNV向人群的溢出提供了分子水平的解释。与来自东南亚和澳大利亚的致病性亨德拉病毒（HeV）和尼帕病毒（NiV）相关的非洲亨尼帕病毒（HNV）的发现提出了一个开放式的健康风险。在考虑溢出和感染人群的可能性时，新兴非洲HNV在进入宿主细胞阶段对细胞受体的使用是一个关键参数。来自加纳蝙蝠分离物（GhV-G）的附着糖蛋白与亚洲NiV-G/HeV-G具有<30%的序列同一性。在这里，通过对GhV-G的功能和结构分析，我们展示了这种非洲HNV如何靶向与亚洲HNV相同的人类细胞表面受体（ephrinB 2）。我们首先从晶体学上表征了这种病毒-受体相互作用。与现存的HNV-G-ephrinB 2结构相比，GhV-G受体结合结构域的六叶β螺旋桨支架存在显著的结构变化，但结合ephrinB 2的希腊关键折叠没有变化。分析揭示了一个令人惊讶的保守模式ephrinB 2的相互作用，反映了一个正在进行的进化限制之间的地理上的远端和遗传学上的分歧HNV，以保持ephrinB 2的功能识别病毒的主机进入。有趣的是，与NiV-G/HeV-G不同，我们不能检测到GhV-G与ephrinB 3的结合。比较结构-功能分析进一步揭示了HNV-G功能的几个显著特征：第二ephrinB 2相互作用位点，其有助于更有效地ephrinB 2介导的进入NiV-G相对于GhV-G和在GhV-G的C末端的同源残基（在亚洲HNV-G中不存在），其对于有效的受体诱导的融合而不是受体结合本身是至关重要的。这些数据提供了分子水平的细节，以评估非洲HNV蔓延到人群中的可能性。
Significance African 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 β-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.