Dimeric Architecture of the Hendra Virus Attachment Glycoprotein: Evidence for a Conserved Mode of Assembly
Dimeric Architecture of the Hendra Virus Attachment Glycoprotein: Evidence for a Conserved Mode of Assembly
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DOI：
10.1128/jvi.00317-10
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发表时间：
2010-06-01
影响因子：
5.4
通讯作者：
Stuart, David I.
中科院分区：
文献类型：
--
作者：
Bowden, Thomas A.;Crispin, Max;Stuart, David I.
亨德拉病毒是副粘病毒科中的一种负义单链RNA病毒，其与尼帕病毒一起形成亨尼帕病毒属。蝙蝠传播的亨德拉病毒感染会导致人类死亡率高的疾病。我们确定了晶体结构的unliganded六叶β-螺旋桨域，并将其与以前报道的亨德拉病毒附着糖蛋白（HeV-G）与其细胞受体肝配蛋白-B2复合体的结构进行了比较。如对相关的未配体的尼帕病毒结构所观察到的，在受体接合之前，Glu 579-Pro590和Lys 236-Ala 245肝配蛋白结合环中存在可塑性。这些数据表明，亨尼帕病毒附着糖蛋白在受体结合后经历共同的结构转变，并进一步定义了抗亨尼帕病毒药物设计的结构模板。我们的分析还提供了实验证据的HeV-G，表现出惊人的相似性，在相关的副粘病毒受体结合糖蛋白的晶体结构中观察到的二聚体的安排。该二聚体的生物学相关性进一步得到副粘病毒糖基化位点位置分析的支持。在HeV-G中，这些位点远离推定的二聚体界面，并且在寡聚化时仍然可以被α-甘露糖苷酶加工。因此，我们提出，二聚体组装的整体模式是保守的所有副粘病毒;然而，尽管二聚体的几何结构与结合柔性聚糖受体的那些病毒相当相似，显著（最多60个）和不同的子单元包装重新配置（与二聚体界面尺寸的显著减小相关）伴随着向高-亨德拉病毒和麻疹病毒的亲和蛋白受体结合。
Hendra virus is a negative-sense single-stranded RNA virus within the Paramyxoviridae family which, together with Nipah virus, forms the Henipavirus genus. Infection with bat-borne Hendra virus leads to a disease with high mortality rates in humans. We determined the crystal structure of the unliganded six-bladed beta-propeller domain and compared it to the previously reported structure of Hendra virus attachment glycoprotein (HeV-G) in complex with its cellular receptor, ephrin-B2. As observed for the related unliganded Nipah virus structure, there is plasticity in the Glu579-Pro590 and Lys236-Ala245 ephrin-binding loops prior to receptor engagement. These data reveal that henipaviral attachment glycoproteins undergo common structural transitions upon receptor binding and further define the structural template for antihenipaviral drug design. Our analysis also provides experimental evidence for a dimeric arrangement of HeV-G that exhibits striking similarity to those observed in crystal structures of related paramyxovirus receptor-binding glycoproteins. The biological relevance of this dimer is further supported by the positional analysis of glycosylation sites from across the paramyxoviruses. In HeV-G, the sites lie away from the putative dimer interface and remain accessible to alpha-mannosidase processing on oligomerization. We therefore propose that the overall mode of dimer assembly is conserved for all paramyxoviruses; however, while the geometry of dimerization is rather closely similar for those viruses that bind flexible glycan receptors, significant (up to 60) and different reconfigurations of the subunit packing (associated with a significant decrease in the size of the dimer interface) have accompanied the independent switching to high-affinity protein receptor binding in Hendra and measles viruses.