RGD-containing peptides inhibit fibrinogen binding to platelet αIIbβ3 by inducing an allosteric change in the amino-terminal portion of αIIb
RGD-containing peptides inhibit fibrinogen binding to platelet αIIbβ3 by inducing an allosteric change in the amino-terminal portion of αIIb
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DOI：
10.1074/jbc.m011511200
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发表时间：
2001-04-27
影响因子：
4.8
通讯作者：
Poncz, M
中科院分区：
文献类型：
--
作者：
Basani, RB;D'Andrea, G;Poncz, M
为了确定大鼠α（II B）β（3）对含RGD肽的抑制不敏感的分子基础，在中国仓鼠卵巢细胞和B淋巴细胞中表达人和大鼠α（II B）β（3）的杂交体和α（II B）β（3）的嵌合体，其中α（II B）由人和大鼠α（II B）的部分组成，并测量四肽RGDS抑制纤维蛋白原与各种形式的α（IIb）β（3）结合的能力。这些测量结果表明，调节α（IIb）β（3）对RGDS敏感性的序列位于α（IIb）的7个氨基末端重复序列中。此外，用相应的人类序列替换大鼠α（IIb）的前三个或四个（但不是前两个）重复序列增强了对RGDS的敏感性，而用相应的大鼠序列替换人α（IIb）的前两个或三个重复序列几乎没有影响。然而，RGDS与表达α（IIb）β（3）的中国仓鼠卵巢细胞结合，无论异二聚体中的α（IIb）是人、大鼠还是大鼠-人嵌合体。这些结果表明，决定α（IIb）β（3）对含RGD肽敏感性的序列位于α（IIb）的第三和第四氨基末端重复序列。由于RGDS与人和大鼠α（IIb）β（3）结合，因此结果表明RGDS敏感性的差异是由RGDS结合后这些重复序列中诱导的变构变化的差异引起的。
To determine the molecular basis for the insensitivity of rat alpha (IIb)beta (3) to inhibition by RGD-containing peptides, hybrids of human and rat alpha (IIb)beta (3) and chimeras of alpha (IIb)beta (3) in which alpha (IIb), was composed of portions of human and rat alpha (IIb) were expressed in Chinese hamster ovary cells and B lymphocytes, and the ability of the tetrapeptide RGDS to inhibit fibrinogen binding to the various forms of alpha (IIb)beta (3) was measured. These measurements indicated that sequences regulating the sensitivity of alpha (IIb)beta (3) to RGDS are located in the seven amino-terminal repeats of alpha (IIb). Moreover, replacing the first three or four (but not the first two) repeats of rat alpha (IIb) With the corresponding human sequences enhanced sensitivity to RGDS, whereas replacing the first two or three repeats of human alpha (IIb) with the corresponding rat sequences had little or no effect. Nevertheless, RGDS bound to Chinese hamster ovary cells expressing alpha (IIb)beta (3) regardless whether the alpha (IIb) in the heterodimers was human, rat, or a rat-human chimera, These results indicate that the sequences determining the sensitivity of alpha (IIb)beta (3) to RGD-containing peptides are located in the third and fourth amino-terminal repeats of alpha (IIb). Because RGDS binds to both human and rat alpha (IIb)beta (3), the results suggest that differences in RGDS sensitivity result from differences in the allosteric changes induced in these repeats following RGDS binding.