Structural basis for Gas6-Axl signalling
Structural basis for Gas6-Axl signalling
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DOI：
10.1038/sj.emboj.7600912
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发表时间：
2006-01-11
期刊：
影响因子：
11.4
通讯作者：
Hohenester, E
中科院分区：
文献类型：
--
作者：
Sasaki, T;Knyazev, PG;Hohenester, E
Axl家族的受体酪氨酸激酶被维生素K依赖性蛋白Gas 6激活。Axl信号传导在癌症、精子发生、免疫和血小板功能中起重要作用。最小的人Gas 6/Axl复合物在3.3埃分辨率下的晶体结构揭示了2：2化学计量的组装，其中Axl胞外域的两个免疫球蛋白样结构域通过Gas 6的第一层粘连蛋白G样结构域交联，没有直接的Axl/Axl或Gas 6/Gas 6接触。有两种不同的Gas 6/Axl接触，大小非常不同，两者都具有边缘β链之间的相互作用。基于结构的诱变，蛋白结合试验和受体活化实验表明，生产性跨膜信号传导所需的主要和次要Gas 6结合位点。Gas 6介导的Axl二聚化可能分两步发生，首先形成高亲和力的1：1 Gas 6/Axl复合物。只有次要的Gas 6结合位点在其他Axl家族受体Sky/Tyro 3和Mer中高度保守。建议在主要接触的特异性，导致带电和非极性残基的分离，相对的新形成的β-片层的面。
Receptor tyrosine kinases of the Axl family are activated by the vitamin K-dependent protein Gas6. Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 angstrom resolution of a minimal human Gas6/Axl complex reveals an assembly of 2: 2 stoichiometry, in which the two immunoglobulin-like domains of the Axl ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts of very different size, both featuring interactions between edge beta-strands. Structure-based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling. Gas6-mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1: 1 Gas6/Axl complex forming first. Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed beta-sheet.