Characterization of calcium- and integrin-binding protein 1 (CIB 1) knockout platelets: Potential compensation by CIB family members
Characterization of calcium- and integrin-binding protein 1 (CIB 1) knockout platelets: Potential compensation by CIB family members
复制标题
DOI：
10.1160/th08-06-0351
复制
发表时间：
2008-11-01
影响因子：
6.7
通讯作者：
Parise, Leslie V.
中科院分区：
文献类型：
--
作者：
DeNofrio, Jan C.;Yuan, Weiping;Parise, Leslie V.
血小板聚集需要α IIb β 3整联蛋白的活化，这是一种由整联蛋白胞质尾调控的事件。CIB 1与整联蛋白α IIb亚基的胞质尾区结合。先前在鼠巨核细胞中的过表达和敲低研究表明，CIB 1抑制整合素α IIb β 3活化。在这里，我们分析了Cib 1（-/-）小鼠，以确定CIB 1在体外和体内血小板中的功能。我们发现，虽然这些小鼠没有明显的血小板表型，CIB 1同源物CIB 3的mRNA水平在CIB 1（-/-）巨核细胞增加。体外结合实验表明，重组CIB 1、CIB-2和CIB-3能特异性地与一个allb胞质尾肽结合。随后的蛋白质建模实验表明，CIB 1-3各自具有高度保守的疏水结合口袋。因此，存在通过这些CIB家族成员补偿CIB 1损失的可能性，从而防止CIB 1（-/-）小鼠中的病理性血栓形成。
Platelet aggregation requires activation of the alpha IIb beta 3 integrin,an event regulated by the integrin cytoplasmic tails. CIB1 binds to the cytoplasmic tail of the integrin alpha IIb subunit. Previous overexpression and knockdown studies in murine megakaryocytes demonstrated that CIB1 inhibits integrin alpha IIb beta 3 activation. Here we analyzed Cib1(-/-) mice to determine the function of CIB1 in platelets in vitro and in vivo. We found that although these mice had no overt platelet phenotype, mRNA level of CIB1 homolog CIB3 was increased in Cib1(-/-) megakaryocytes. In vitro binding experiments showed that recombinant CIB1,-2 and -3 bound specifically to an allb cytoplasmic tail pepticle. Subsequent protein modeling experiments indicated that CIBs 1-3 each have a highly conserved hydrophobic binding pocket. Therefore, the potential exists for compensation for the loss of CIB1 by these CIB family members, thereby preventing pathologic thrombus formation in Cib1(-/-) mice.