Sweeney Shawn M, Orgel Joseph P, Fertala Andrzej, McAuliffe Jon D, Turner Kevin R, Di Lullo Gloria A, Chen Steven, Antipova Olga, Perumal Shiamalee, Ala-Kokko Leena, Forlino Antonella, Cabral Wayne A, Barnes Aileen M, Marini Joan C, San Antonio James D
Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
J Biol Chem. 2008 Jul 25;283(30):21187-97. doi: 10.1074/jbc.M709319200. Epub 2008 May 15.
Type I collagen, the predominant protein of vertebrates, polymerizes with type III and V collagens and non-collagenous molecules into large cable-like fibrils, yet how the fibril interacts with cells and other binding partners remains poorly understood. To help reveal insights into the collagen structure-function relationship, a data base was assembled including hundreds of type I collagen ligand binding sites and mutations on a two-dimensional model of the fibril. Visual examination of the distribution of functional sites, and statistical analysis of mutation distributions on the fibril suggest it is organized into two domains. The "cell interaction domain" is proposed to regulate dynamic aspects of collagen biology, including integrin-mediated cell interactions and fibril remodeling. The "matrix interaction domain" may assume a structural role, mediating collagen cross-linking, proteoglycan interactions, and tissue mineralization. Molecular modeling was used to superimpose the positions of functional sites and mutations from the two-dimensional fibril map onto a three-dimensional x-ray diffraction structure of the collagen microfibril in situ, indicating the existence of domains in the native fibril. Sequence searches revealed that major fibril domain elements are conserved in type I collagens through evolution and in the type II/XI collagen fibril predominant in cartilage. Moreover, the fibril domain model provides potential insights into the genotype-phenotype relationship for several classes of human connective tissue diseases, mechanisms of integrin clustering by fibrils, the polarity of fibril assembly, heterotypic fibril function, and connective tissue pathology in diabetes and aging.
I型胶原蛋白是脊椎动物的主要蛋白质，它与III型和V型胶原蛋白以及非胶原蛋白分子聚合形成大型的缆索状纤维，但这种纤维如何与细胞及其他结合伴侣相互作用仍知之甚少。为了有助于揭示胶原蛋白结构与功能的关系，构建了一个数据库，其中包括数百个I型胶原蛋白配体结合位点以及在纤维二维模型上的突变。对功能位点分布的直观检查以及对纤维上突变分布的统计分析表明，它被组织成两个结构域。“细胞相互作用结构域”被认为可调节胶原蛋白生物学的动态方面，包括整合素介导的细胞相互作用和纤维重塑。“基质相互作用结构域”可能发挥结构作用，介导胶原蛋白交联、蛋白聚糖相互作用和组织矿化。利用分子建模将二维纤维图谱中的功能位点和突变位置叠加到原位胶原蛋白微纤维的三维X射线衍射结构上，表明天然纤维中存在结构域。序列搜索显示，主要的纤维结构域元件在I型胶原蛋白的进化过程中以及在软骨中占主导地位的II型/ XI型胶原蛋白纤维中都是保守的。此外，纤维结构域模型为几类人类结缔组织疾病的基因型-表型关系、纤维对整合素聚集的机制、纤维组装的极性、异型纤维功能以及糖尿病和衰老中的结缔组织病理学提供了潜在的见解。
