Binding of platelet glycoprotein Ibbeta through the convex surface of leucine-rich repeats domain of glycoprotein IX.
Binding of platelet glycoprotein Ibbeta through the convex surface of leucine-rich repeats domain of glycoprotein IX.
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DOI：
10.1111/j.1538-7836.2009.03536.x
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发表时间：
2009-09
期刊：
影响因子：
--
通讯作者：
Li R
中科院分区：
文献类型：
--
作者：
Mo X;Nguyen NX;McEwan PA;Zheng X;López JA;Emsley J;Li R
血小板糖蛋白（GP）Ib-IX复合物由GPIbα、GPIbβ和GPIX亚基组装而成的机制尚不完全清楚。在该复合物中，GPIbβ和GPIX亚基的胞外域均含有两个富含亮氨酸的重复序列（LRR），并且具有高度的序列相似性。然而，它们在稳定性上有明显的不同，妨碍了对它们之间相互作用的进一步分析。在LRR结构分析的指导下，我们报道了一个折叠良好的Ibβ/IX嵌合体及其在解剖GPIX功能中的用途。在该嵌合体中，可能构成GPIbβ胞外域推定凸面的三个非连续序列被其GPIX对应物取代。与GPIX胞外域不同，GPIb β能从转染的中国仓鼠卵巢细胞中分泌并折叠成稳定的构象。此外，用Ibβ/IX嵌合体取代GPIX的胞外域，而不是GPIbβ胞外域，保留了GPIb β与GPIbβ的相互作用，如其天然样GPIbβ诱导的表面表达和免疫共沉淀增加所证明的。在全长亚基的情况下，GPIX中LRR结构域的假定凸面足以介导其与GPIbβ的缔合。
The mechanism of assembly of the platelet glycoprotein (GP) Ib-IX complex from GPIbα, GPIbβ and GPIX subunits is not entirely clear. In this complex, ectodomains of both GPIbβ and GPIX subunits contain two leucine-rich repeats (LRR) and share high sequence similarity. However, they differ noticeably in stability, hampering further analysis of their interaction. Guided by analysis of the LRR structure, we report a well-folded Ibβ/IX chimera and its usage in dissecting GPIX function. In this chimera, three non-contiguous sequences that may constitute the putative convex surface of the GPIbβ ectodomain are replaced by their GPIX counterparts. Like GPIbβ but unlike GPIX ectodomain, it can secrete from transfected Chinese hamster ovary cells and fold into a stable conformation. Furthermore, replacing the ectodomain in GPIX with the Ibβ/IX chimera, but not the GPIbβ ectodomain, preserved its interaction with GPIbβ as demonstrated by its native-like GPIbβ-induced increase in surface expression and coimmunoprecipitation. The putative convex surface of the LRR domain in GPIX is sufficient, in the context of full-length subunit, to mediate its association with GPIbβ.
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