Structure of reovirus sigma1 in complex with its receptor junctional adhesion molecule-A.
Structure of reovirus sigma1 in complex with its receptor junctional adhesion molecule-A.
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DOI：
10.1371/journal.ppat.1000235
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发表时间：
2008-12
期刊：
影响因子：
6.7
通讯作者：
Stehle T
中科院分区：
文献类型：
--
作者：
Kirchner E;Guglielmi KM;Strauss HM;Dermody TS;Stehle T
病毒附着于特定的宿主受体是病毒感染的第一步，并且在靶细胞的选择中起着重要的作用。哺乳动物呼肠孤病毒是研究病毒致病机制的非常有用的实验模型，并显示出作为溶瘤剂和疫苗载体的前景。呼肠孤病毒通过与碳水化合物和免疫球蛋白超家族成员连接粘附分子-A（JAM-A）结合来接合细胞。JAM-A作为同源二聚体存在于细胞表面，该同源二聚体通过其N-末端免疫球蛋白样结构域之间的广泛接触形成。我们报告了呼肠孤病毒附着蛋白σ1与可溶性形式的JAM-A复合的晶体结构。σ1蛋白破坏JAM-A二聚体，通过与用于JAM-A同源二聚化几乎相同的界面接合单个JAM-A分子。因此，呼肠孤病毒利用免疫球蛋白超家族受体的粘附性质，通过篡夺该分子的配体结合位点来附着到细胞表面。σ1与JAM-A之间相互作用的解离常数（KD）比JAM-A分子之间的亲均相互作用的解离常数低1，000倍，表明JAM-A强烈偏好σ1作为配体。通过基于质粒的反向遗传学工程化的呼肠孤病毒突变体的分析揭示了结合JAM-A和培养细胞的感染性所需的σ1中的残基。这些研究定义了呼肠孤病毒细胞附着的生物物理机制，并为操纵呼肠孤病毒嗜性以增强载体靶向提供了平台。哺乳动物正呼肠孤病毒是研究病毒-受体相互作用和病毒发病机制的有用模型。它们在结构上与腺病毒密切相关，并且具有相似的细胞附着和进入机制。呼肠孤病毒的受体，连接粘附分子-A（JAM-A），是细胞连接的组分，也被猫杯状病毒用作受体。为了更好地理解病毒如何接合细胞受体，我们确定了与JAM-A结合的呼肠孤病毒附着蛋白σ1的结构。该结构提供了对相互作用的生物学功能的理解，并产生了可能使呼肠孤病毒靶向替代受体的信息。由于病毒结合的受体库对确定哪种类型的细胞被感染有重要贡献，因此这种靶向在疫苗或治疗应用的基因递送中起着至关重要的作用。新的癌症治疗方法包括使用病毒（包括呼肠孤病毒）来裂解肿瘤细胞。关于呼肠孤病毒在原子水平上附着于细胞受体的新知识将有助于利用这种病毒的治疗潜力。
Viral attachment to specific host receptors is the first step in viral infection and serves an essential function in the selection of target cells. Mammalian reoviruses are highly useful experimental models for studies of viral pathogenesis and show promise as vectors for oncolytics and vaccines. Reoviruses engage cells by binding to carbohydrates and the immunoglobulin superfamily member, junctional adhesion molecule-A (JAM-A). JAM-A exists at the cell surface as a homodimer formed by extensive contacts between its N-terminal immunoglobulin-like domains. We report the crystal structure of reovirus attachment protein σ1 in complex with a soluble form of JAM-A. The σ1 protein disrupts the JAM-A dimer, engaging a single JAM-A molecule via virtually the same interface that is used for JAM-A homodimerization. Thus, reovirus takes advantage of the adhesive nature of an immunoglobulin-superfamily receptor by usurping the ligand-binding site of this molecule to attach to the cell surface. The dissociation constant (KD) of the interaction between σ1 and JAM-A is 1,000-fold lower than that of the homophilic interaction between JAM-A molecules, indicating that JAM-A strongly prefers σ1 as a ligand. Analysis of reovirus mutants engineered by plasmid-based reverse genetics revealed residues in σ1 required for binding to JAM-A and infectivity of cultured cells. These studies define biophysical mechanisms of reovirus cell attachment and provide a platform for manipulating reovirus tropism to enhance vector targeting. Mammalian orthoreoviruses (reoviruses) are useful models for studies of virus–receptor interactions and viral pathogenesis. They are closely related in structure to adenoviruses and share similar mechanisms of cell attachment and entry. The receptor for reovirus, junctional adhesion molecule-A (JAM-A), is a component of cellular junctions and also used as a receptor by feline calicivirus. To better understand how viruses engage cellular receptors, we determined the structure of reovirus attachment protein σ1 bound to JAM-A. The structure provides an understanding of the biological function of the interaction and yields information that may enable targeting of reovirus to alternate receptors. Since the repertoire of receptors bound by a virus contributes importantly to determining which types of cells are infected, such targeting plays an essential role in gene delivery for vaccine or therapeutic applications. New cancer therapy approaches include the use of viruses, including reovirus, to lyse tumor cells. New knowledge about reovirus attachment to cellular receptors at an atomic level will help to harness the therapeutic potential of this virus.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.4
作者：
FRASER, RDB;FURLONG, DB;STEVEN, AC
通讯作者：
STEVEN, AC
影响因子：
4.8
作者：
Guglielmi, Kristen M.;Kirchner, Eva;Dermody, Terence S.
通讯作者：
Dermody, Terence S.
影响因子：
5.6
作者：
Calvo, PG;Fox, GC;van Raaij, MJ
通讯作者：
van Raaij, MJ
影响因子：
3.7
作者：
Ishii, K;Ueda, Y;Miyamura, T
通讯作者：
Miyamura, T