Specificity of the VP1 GH loop of foot-and-mouth disease virus for αv integrins
Specificity of the VP1 GH loop of foot-and-mouth disease virus for αv integrins
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DOI：
10.1128/jvi.00577-06
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发表时间：
2006-10-01
影响因子：
5.4
通讯作者：
Jackson, Terry
中科院分区：
文献类型：
--
作者：
Burman, Alison;Clark, Stuart;Jackson, Terry
口蹄疫病毒（FMDV）可以使用许多整合素作为受体来启动感染。与整合素的连接是由位于 VP1 GH 环上的高度保守的精氨酸-甘氨酸-天冬氨酸 (RGD) 三肽介导的。该环的其他残基也是保守的，可能有助于整合素结合。在本研究中，我们使用了 17 聚体肽，其序列对应于 O 型 FMDV VP1 的 GH 环，作为整合素介导的病毒结合和感染的竞争者。通过该肽的丙氨酸取代鉴定出 RGD 之后的第一个和第四个位置的亮氨酸（RGD + 1 和 RGD + 4 位点）是抑制 alpha v beta 6 或 alpha v beta 8 介导的病毒结合和感染的关键，但不是抑制病毒与 alpha v beta 3 结合的关键。我们还表明，FMDV 肽在 RGD + 1 位点含有甲硫氨酸或精氨酸，这反映了 FMDV 中看到的自然序列变异。血清型，是 α v β 6 的有效抑制剂。相反，虽然含有 RGDM 的肽对 α v β 8 有效，但含有 RGDR 的肽则不然。这些观察结果通过显示含有RGDR基序的病毒使用αvβ8作为感染受体的效率低于αvβ6而得到证实。最后，有证据表明 alpha v beta 3 是 O 型 FMDV 感染的不良受体。综上所述，我们的数据表明，FMDV 的整合素结合环很可能已经进化为与 alpha v beta 6 的结合，其亲和力高于与 alpha v beta 3 和 alpha v beta 8 的结合。
Foot-and-mouth disease virus (FMDV) can use a number of integrins as receptors to initiate infection. Attachment to the integrin is mediated by a highly conserved arginine-glycine-aspartic acid (RGD) tripeptide located on the GH loop of VP1. Other residues of this loop are also conserved and may contribute to integrin binding. In this study we have used a 17-mer peptide, whose sequence corresponds to the GH loop of VP1 of type O FMDV, as a competitor of integrin-mediated virus binding and infection. Alanine substitution through this peptide identified the leucines at the first and fourth positions following RGD (RGD + 1 and RGD + 4 sites) as key for inhibition of virus binding and infection mediated by alpha v beta 6 or alpha v beta 8 but not for inhibition of virus binding to alpha v beta 3. We also show that FMDV peptides containing either methionine or arginine at the RGD + 1 site, which reflects the natural sequence variation seen across the FMDV serotypes, are effective inhibitors for alpha v beta 6. In contrast, although RGDM-containing peptides were effective for alpha v beta 8, RGDR-containing peptides were not. These observations were confirmed by showing that a virus containing an RGDR motif uses alpha v beta 8 less efficiently than alpha v beta 6 as a receptor for infection. Finally, evidence is presented that shows alpha v beta 3 to be a poor receptor for infection by type O FMDV. Taken together, our data suggest that the integrin binding loop of FMDV has most likely evolved for binding to alpha v beta 6 with a higher affinity than to alpha v beta 3 and alpha v beta 8.