New insights into integrin-ligand interaction
New insights into integrin-ligand interaction
复制标题
DOI：
10.1172/jci119408
复制
发表时间：
1997-05-15
影响因子：
15.9
通讯作者：
Liddington, RC
中科院分区：
文献类型：
--
作者：
Loftus, JC;Liddington, RC
整合素介导的细胞-细胞和细胞-基质黏附是多种生理过程的根源。要了解整合素-配体相互作用的分子机制，需要确定大分子整合素配体内的识别位点以及整合素受体内的配体接触点。整合素配体中的一些离散识别序列已经被鉴定和表征。基于其中几个识别序列的高分辨率结构，一个新出现的主题是，这些识别位点由短的多肽序列组成，这些短的多肽序列呈现在伯链(1-3)之间延伸的柔性环上。相比之下，对整合素受体中定义配体识别和特异性的位置的了解出现得较慢。这在一定程度上是由于这些大的异二聚体分子的复杂性，它们的配体结合亲和力的动态调节，以及它们的变构潜力。人们普遍认为整合素含有多个配体接触位点，因为在ɑ和？亚基中都发现了重要区域和特定残基。这三个主要区域是ɑ亚基I-结构域，ɑ亚基的7个NH_2-末端重复序列，以及一个似乎是ɑ亚单位I-结构域的功能和结构同源的保守区。原子分辨晶体结构只存在于ɑ亚单位I-结构域(4，5)，但最近对其他两个结构域的假设原子模型提供了根据突变和生化数据构建整合素配体结合和变构的四元模型的机会。ɑ亚单位I-结构域。ɑ亚基I-结构域的第一个晶体结构表明它采用了二核苷酸结合折叠，两侧有一个中心平行的？片层被ɑ螺旋包围(5)。这种折叠在细胞内的磷酸转移酶中非常常见，但以前在细胞外区域中没有观察到。在这类折叠中，分子的官能面总是位于波片的COOH-末端。在ɑ亚基的I-结构域中，存在一个独特的二价阳离子配位球，被命名为金属离子依赖的粘连
Integrin mediated cell–cell and cell–matrix adhesion is at the root of a diverse range of physiological processes. An understanding of the molecular mechanisms of integrin–ligand interaction requires identification of the recognition sites within the macromolecular integrin ligands as well as the ligand contact points within the integrin receptor. A number of discrete recognition sequences within integrin ligands have been identified and characterized. Based on high resolution structures for several of these recognition sequences, an emerging theme is that these recognition sites consist of short peptide sequences presented on extended flexible loops between ß strands (1–3). By contrast, an understanding of the sites within the integrin receptors that define ligand recognition and specificity has been slower to emerge. This is due in part to the complexity of these large heterodimeric molecules, the dynamic modulation of their ligand binding affinity, and their potential for allostery. It is generally accepted that integrins contain multiple ligand contact sites, as essential regions and specific residues have been identified in both the ɑ and ß subunits. The three major regions are the ɑ subunit I-domain, the seven NH2-terminal repeats of the ɑ subunit, and a conserved region of the ß subunits that appears to be a functional and structural homolog of the ɑ subunit I-domain. Atomic resolution crystal structures exist only for the ɑ subunit I-domain (4, 5), but recent hypothetical atomic models of the other two domains present an opportunity to build a quaternary model of integrin ligand binding and allostery in the light of the mutagenesis and biochemical data.The ɑ subunit I-domain. The first crystal structure of an ɑ subunit I-domain demonstrated that it adopts the dinucleotide-binding fold, with a central parallel ß sheet surrounded on both sides by ɑ helices (5). This fold is very common among intracellular phosphoryl transfer enzymes, but has not been observed previously in an extracellular domain. In this class of fold, the functional surface of the molecules always lies at the COOH-terminal end of the ß sheet. In the ɑ subunit I-domain, a unique divalent cation coordination sphere is located there and has been designated the metal ion–dependent adhesion