A naturally occurring mutation near the amino terminus of αIIb defines a new region involved in ligand binding to αIIbβ3
A naturally occurring mutation near the amino terminus of αIIb defines a new region involved in ligand binding to αIIbβ3
复制标题
DOI：
10.1182/blood.v95.1.180.001k16_180_188
复制
发表时间：
2000-01-01
期刊：
影响因子：
20.3
通讯作者：
Poncz, M
中科院分区：
文献类型：
--
作者：
Basani, RB;French, DL;Poncz, M
血小板表面功能性αIIbβ3复合体表达减少导致Glanzmann血栓减少。我们在3个不同种族的Glanzmann血小板减少症家系中发现了αIIb突变(P145)，受累的门诺族和荷兰患者分别是P(145)A替换纯合子和双重杂合，而中国患者是(PL)-L-145替换双重杂合。这些突变影响其血小板表面αIIbβ3受体的表达水平，这一点已通过将αIIb(P145A)和β3构建物共转染COS-1细胞而得到证实。每个突变还会削弱受影响血小板上的αIIbβ3与配体相互作用的能力。此外，当αIIb(P145a)和β3在中国仓鼠卵巢细胞中稳定共表达时，细胞表面很容易检测到αIIbβ3，但激活的单抗PT25-2激活αIIbβ3后，细胞不能黏附于固定化的纤维蛋白原，也不能结合可溶性异硫氰酸酯-纤维蛋白原，但与与αIIb结合的多肽LSARLAF孵育后，诱导了PF4的分泌，表明突变的αIIbβ3保持了介导内外信号转导的能力。这些研究表明，涉及αIIb(P145)的突变削弱了αIIbβ3的表面表达，并且αIIb(P145A)突变取消了与激活的整合素的配体结合。对其他表型相似的αIIb突变的比较分析表明，这些突变可能聚集在αIIb表面的单个区域，并可能定义一个影响配体结合的区域。(C)2000年，由美国血液病学会提供。
Decreased expression of functional alpha IIb beta 3 complexes on the platelet surface produces Glanzmann thrombasthenia, We have identified mutations of alpha IIb(P145) in 3 ethnically distinct families affected by Glanzmann thrombasthenia, Affected Mennonite and Dutch patients were homozygous and doubly heterozygous, respectively, for a P(145)A substitution, whereas a Chinese patient was doubly heterozygous for a (PL)-L-145 substitution. The mutations affect expression levels of surface alpha IIb beta 3 receptors on their platelets, which was confirmed by co-transfection of alpha IIb(P145A) and beta 3 cDNA constructs in COS-1 cells. Each mutation also impaired the ability of alpha IIb beta 3 on affected platelets to interact with ligands. Moreover, when alpha IIb(P145A) and beta 3 were stably coexpressed in Chinese hamster ovary cells, alpha IIb beta 3 was readily detected on the cell surface, but the cells were unable to adhere to immobilized fibrinogen or to bind soluble fluorescein isothiocyanate-fibrinogen after alpha IIb beta 3 activation by the activating monoclonal antibody PT25-2, Nonetheless, incubating affected platelets with the peptide LSARLAF, which binds to alpha IIb, induced PF4 secretion, indicating that the mutant alpha IIb beta 3 retained the ability to mediate outside-in signaling. These studies indicate that mutations involving alpha IIb(P145) impair surface expression of alpha IIb beta 3 and that the alpha IIb(P145A) mutation abrogates ligand binding to the activated integrin, A comparative analysis of other alpha IIb mutations with a similar phenotype suggests that these mutations may cluster into a single region on the surface of the alpha IIb and may define a domain influencing ligand binding. (C) 2000 by The American Society of Hematology.