Biomolecular Mechanics of Collagen Monomers And Fibrils

描述(申请人提供)：生物力学稳定性和强度 长期以来，结缔组织一直被认为是分子间共价的 胶原蛋白单体之间的交联度。I型胶原蛋白，主要成分 骨、肌腱、皮肤和血管系统，通常是异三聚体，由 两个Al(I)链和单个a2(I)链，[Al(I)2a2(I)]。然而，类型I OIM小鼠体内的胶原蛋白仅由Al(I)同源三聚体[Al(I)3]组成 (由a2(I)基因零突变所致)。OIM小鼠是一个极好的模型 用于检查a2(I)链的功能必要性的系统。我们 假设a2(I)链的缺失扰乱了胶原纤维 形成、胶原-胶原相互作用以及分子内和分子间 交联性，损害骨的结构和生物力学的完整性 结缔组织。使用OIM小鼠进行的活体研究表明， I型胶原同源三聚体的存在显著降低了 骨骼、肌腱、皮肤和主动脉的生物力学完整性。进一步的分析使用 OIM小鼠提示非共价胶原分子内和分子间相互作用 而组织可能是调节机械完整性的关键因素 而不是胶原蛋白的交联。这些结果对教条提出了质疑 胶原蛋白单体之间的共价分子间交联是主要的 纤维稳定性和生物力学完整性的决定因素 架构，并迫使我们考虑其他因素和相互作用，例如 单个胶原单体的固有机械性能和 蛋白质之间的非共价相互作用。应用领域的最新进展 原子力显微镜的发展使得分析固有的力学性能成为可能 单个生物分子的性质和分子-分子相互作用。我们 建议使用原子力显微镜来定义a2(I)链在 胶原蛋白单体固有的机械完整性，2)非共价 胶原蛋白-胶原蛋白相互作用，以及3)在固有的机械完整性 胶原纤维，以及提供了一个强大的新工具来定义和 了解纤维性胶原突变等的发病机制 细胞外基质成分及其在结缔组织疾病中的作用。

DESCRIPTION (provided by applicant): Biomechanical stability and strength of connective tissues have long been attributed to covalent intermolecular crosslinks between collagen monomers. Type I collagen, a major component of bone, tendon, skin, and the vasculature, is normally heterotrimeric, consisting of two al (I) chains and a single a2(I) chain, [al(I)2a2(I)]. However, type I collagen in oim mice is exclusively composed of al(I) homotrimers, [al(I)3] (result of a null mutation in the a2(I) gene). Oim mice are a superb model system for examining the functional necessity of the a2(I) chain. We hypothesize that the absence of a2(I) chains perturbs collagen fibril formation, collagen-collagen interactions, and intra- and inter-molecular crosslinking, compromising the structural and biomechanical integrity of connective tissues. In vivo studies using oim mice demonstrate that the presence of type I collagen homotrimers significantly decreases the biomechanical integrity of bone, tendon, skin and aorta. Further analyses using oim mice suggest non-covalent collagen intra- and intermolecular interactions and organization maybe the critical factors regulating mechanical integrity rather than collagen crosslinking. These results question the dogma that covalent intermolecular crosslinks between collagen monomers are the principal determinants of stability and biomechanical integrity of the fibrillar architecture, and compel us to consider other forces and interactions, such as the inherent mechanical properties of individual collagen monomers and non-covalent protein-protein interactions. Recent advances in the application of atomic force microscopy now make it possible to analyze inherent mechanical properties of single biomolecules and molecule-molecule interactions. We propose to use atomic force microscopy to define the role of a2(I) chains 1) in the inherent mechanical integrity of collagen monomers, 2) in non-covalent collagen-collagen interactions, and 3) in the inherent mechanical integrity of collagen fibrils, as well as provide a powerful new tool for defining and understanding the pathogenesis of fibrillar collagen mutations and other extracellular matrix components and their role in connective tissue disease.