Development of a structural model for the cytoplasmic domain of an integrin.
Development of a structural model for the cytoplasmic domain of an integrin.
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整合素胞质结构域结构模型的开发。
DOI：
10.1093/protein/10.12.1395
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Plow,EF
中科院分区：
文献类型：
--
作者：
Haas,TA;Plow,EF
整合素异二聚体的细胞质尾部在控制整合素的激活状态和传递细胞内信号方面发挥着核心作用。尽管长度很短，但尚未确定任何整合素胞质结构域的结构。因此，生成了主要血小板整合素α(IIb)β3细胞质结构域的分子模型，包括单个细胞质尾部、二元αIIb-钙复合物和三元αIIb-β3-钙复合物的模型。利用从结晶蛋白内的短同源序列获得的数据和二级结构预测来编译圆二色光谱的结构分析，以开发每个亚基的起始模型。这些模型经过一系列能量最小化和分子动力学模拟以生成最终模型。预计 AlphaIIb 在其 N 末端是有序的，其 C 末端可以容纳多配位复合物中的阳离子。 beta3 的结构主要由 NPXY 基序处的 β 转角 (beta3 744-747) 决定。当 αIIb 与 beta3 内的不同位点对接时，β3 邻跨膜 (beta3 716-721) 的构象发生了很大改变。通过圆二色性证实该区域是构象“热点”。该近跨膜区域的构象灵活性在整联蛋白中高度保守，是调节信号传导的理想位置。
The cytoplasmic tails of integrin heterodimers play central roles in controlling the activation states of integrins and in transmitting intracellular signals. Despite their short length, no structure of any integrin cytoplasmic domain has been determined. Therefore, molecular models for the cytoplasmic domain of alpha(IIb)beta3, the major platelet integrin, were generated, including models for the individual cytoplasmic tails, the binary alphaIIb-calcium complex, and the ternary alphaIIb-beta3-calcium complex. Structural analysis of circular dichroism spectra were compiled with data obtained from short homologous sequences within crystallized proteins, and with secondary structural predictions to develop starting models for each subunit. These models were subjected to a series of energy minimization and molecular dynamic simulations to generate final models. AlphaIIb was predicted to be ordered at its N-terminus and its C-terminus could accommodate a cation in a multicoordinated complex. The structure of beta3 was dominated by a beta-turn at its NPXY motif (beta3 744-747). In docking of alphaIIb to different sites within beta3, the conformation of the beta3 juxta-transmembrane (beta3 716-721) was greatly altered. This region was confirmed to be a conformational 'hot-spot' by circular dichroism. The conformational flexibility of this juxta-transmembrane region, which is highly conserved amongst integrins, is ideally located to regulate signaling.