Transmembrane signal transduction of the αIIbβ3 integrin
Transmembrane signal transduction of the αIIbβ3 integrin
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DOI：
10.1110/ps.4120102
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发表时间：
2002-07-01
期刊：
影响因子：
8
通讯作者：
Kessler, H
中科院分区：
文献类型：
--
作者：
Gottschalk, KE;Adams, PD;Kessler, H
整合素由α-和β-亚基的非共价结合的二聚体组成。它们在细胞-基质粘附和通过细胞膜的信号转导中起重要作用。信号转导可以通过细胞内蛋白质与整联蛋白的结合来启动。结合导致主要的构象变化。这种变化通过细胞膜传递到细胞外结构域。细胞外结构域对某些配体的亲和力增加;因此至少存在两种状态，低亲和力和高亲和力状态。跨膜结构域的构象和构象变化是我们感兴趣的焦点。我们通过螺旋-螺旋相互作用的全局搜索表明，整合素家族的TM部分能够采用与同型二聚体TM蛋白血型糖蛋白A的结构相似的结构。对于α（IIb）β（3）整联蛋白，该结构基序代表高亲和力状态。通过已知的突变和核磁共振（NMR）研究，α（IIb）β（3）的TM结构域的第二种构象被鉴定为低亲和力状态。通过分子动力学（MD）计算确定这两种状态之间的转变。在这些计算的基础上，我们提出了一个三态机制。
Integrins are composed of noncovalently bound dimers of an alpha- and a beta-subunit. They play an important role in cell-matrix adhesion and signal transduction through the cell membrane. Signal transduction can be initiated by the binding of intracellular proteins to the integrin. Binding leads to a major conformational change. The change is passed on to the extracellular domain through the membrane. The affinity of the extracellular domain to certain ligands increases; thus at least two states exist, a low-affinity and a high-affinity state. The conformations and conformational changes of the transmembrane (TM) domain are the focus of our interest. We show by a global search of helix-helix interactions that the TM section of the family of integrins are capable of adopting a structure similar to the structure of the homodimeric TM protein Glycophorin A. For the alpha(IIb)beta(3) integrin, this structural motif represents the high-affinity state. A second conformation of the TM domain of alpha(IIb)beta(3) is identified as the low-affinity state by known mutational and nuclear magnetic resonance (NMR) studies. A transition between these two states was determined by molecular dynamics (MD) calculations. On the basis of these calculations, we propose a three-state mechanism.