Webb Louise M C, Smith Vincent P, Alcami Antonio
Department of Medicine, University of Cambridge, Cambridge, UK.
FASEB J. 2004 Mar;18(3):571-3. doi: 10.1096/fj.03-0485fje. Epub 2004 Jan 20.
Chemokines are small glycosaminoglycan (GAG) binding proteins that direct the migration of leukocytes by signaling through G protein coupled receptors (GPCR). Many viruses encode proteins that disrupt chemokine responses. The murine gammaherpesvirus-68 gene M3 encodes a chemokine binding protein (vCKBP-3), which has no sequence similarity to chemokine receptors. Initial characterization of vCKBP-3 showed that it inhibits receptor binding and chemokine-induced calcium influx. The structural requirements for the chemokines CXCL8 and CCL2 to bind to vCKBP-3 have been determined. Both chemokines bind to vCKBP-3 via their N-loop, a site that can participate in GAG binding for some chemokines. We have investigated the effect of vCKBP-3 on the interaction of chemokines with GAGs. We found that vCKBP-3 can prevent a range of chemokines from binding to GAGs. Moreover, we also found that vCKBP-3 can displace chemokines from a heparin-coated surface. Together, these data imply that vCKBP-3 can inhibit chemokine activity at two distinct levels. First, it inhibits chemokines from binding to their GPCR. Second, it inhibits their GAG binding and disrupts pre-formed chemokine gradients. This dual ability of vCKBP-3 makes it a more effective inhibitor of chemokine activity.
趋化因子是一类可与小糖胺聚糖（GAG）结合的蛋白质，其通过G蛋白偶联受体（GPCR）发出信号来引导白细胞迁移。许多病毒编码能够破坏趋化因子反应的蛋白质。小鼠γ-疱疹病毒68基因M3编码一种趋化因子结合蛋白（vCKBP-3），它与趋化因子受体没有序列相似性。对vCKBP-3的初步表征表明，它能抑制受体结合以及趋化因子诱导的钙内流。已经确定了趋化因子CXCL8和CCL2与vCKBP-3结合的结构要求。这两种趋化因子均通过其N环与vCKBP-3结合，该位点可参与某些趋化因子与GAG的结合。我们研究了vCKBP-3对趋化因子与GAG相互作用的影响。我们发现vCKBP-3可以阻止一系列趋化因子与GAG结合。此外，我们还发现vCKBP-3可以从肝素包被的表面置换趋化因子。这些数据共同表明，vCKBP-3可以在两个不同水平上抑制趋化因子活性。首先，它抑制趋化因子与其GPCR结合。其次，它抑制趋化因子与GAG的结合并破坏预先形成的趋化因子梯度。vCKBP-3的这种双重能力使其成为趋化因子活性更有效的抑制剂。
