A peptide model to study the Fibril Assembly of collagen triple helix

胶原蛋白是人体内含量最丰富的蛋白质，也是结缔组织的主要成分 与多种疾病有关，包括癌症、发育异常、 动脉粥样硬化和衰老。胶原蛋白不同的分子功能与显著的 胶原蛋白单体--三螺旋--形成不同超分子组合的能力。然而，无论是 胶原蛋白的结构和纤维形成的机制尚不清楚。缺乏这样的能力 知识限制了我们对涉及组织发育和功能的分子事件的了解 阻碍了我们对胶原蛋白相关疾病的病因学的理解。 我们的长期研究目标是了解纤维形成的机制和它的 参与生物过程。纤维样胶原的纤维形成是最常见的 胶原蛋白的自组装过程，是骨骼、皮肤发育和功能的必要步骤 和血管壁。功能性胶原纤维的特征是具有特定的轴向重复结构。 67 nm，称为D周期。最近，我们开发了一种新的细菌表达系统 重组三螺旋，命名为Col108，自我- 是由两种分子性质决定的 特定残基及其在三螺旋上的特定位置；此外，我们认为胶原 突变通过破坏特定的相互作用来损害三螺旋的自组装，从而抑制组织 结构层面的发展。当前提案的直接目标是1)定义具体的 在COL108自组装过程中的分子相互作用，2)以表征致病突变 COL108和3)的自组装以产生形成合成三螺旋多肽的纤维。重大创新 的工作来自于研究胶原蛋白三螺旋的自结合的能力，以及 在纤维形成的水平上描述致病突变的影响。拟议的工作将是 使用诱变方法、生物物理特性和多肽合成相结合的方法进行 化学反应。总的来说，拟议的工作将从根本上加强我们对分子的理解 参与胶原纤维形成的相互作用。这样的知识将导致对 改善纤维形成和增强组织中阳性细胞信号的治疗靶点 发展，以及增强发达组织的功能。这项研究的结果也将 提供了对纤维蛋白的折叠和自结合的一般洞察以及进一步的研究 为生物医学应用设计基于胶原蛋白的微细纤维。 原纤维

Collagen is the most abundant protein in humans and the major component of the connective tissues and is implicated in a wide arrange of disease states including cancer, developmental anomalies, atherosclerosis and aging. The diverse molecular functions of collagen are closely related to the remarkable ability of collagen monomer – the triple helix – to form different supramolecular assemblies. Yet, both the structure and the mechanisms of the fibril formation of collagen remain poorly understood. Lack of such knowledge has limited our understanding of molecular events involved in tissue development and function and hindered our understanding of the etiology of diseases related to collagen. Our long-term goal of research is to understand the mechanism of the fibrillogenesis and its involvement in biological processes. Fibrillogenesis of fibrillar collagens represents one of the most prevalent self-assembly processes of collagen and is the essential step in the development and function of bones, skin and blood vessel walls. The functional collagen fibrils are characterized by a specific axially repeating structure of 67 nm, known as the D-periodicity. Recently we have developed a bacterial expression system of a recombinant triple helix, designated Col108 that self- is determined by both the molecular properties of specific residues and their specific placements along the triple helix; furthermore, we propose that collagen mutations impair the self-assembly of the triple helix by disrupting specific interactions and thus inhibit tissue development at the structural level. The immediate goals of the current proposal are 1) to define the specific molecular interactions during the self-assembly of Col108, 2) to characterize disease causing mutations on the self-assembly of Col108 and 3) to generate fibril forming synthetic triple helical peptides. The major innovation of the proposed work comes from the ability to study the self-association of collagen triple helix, and to characterize the effects of disease causing mutations at the level of fibril formation. The proposed work will be carried out using a combination of mutagenesis approach, biophysical characterizations and peptide synthesis chemistry. Collectively, the proposed work will fundamentally enhance our understanding of the molecular interactions involved in the fibrillogenesis of collagen. Such knowledge will lead to the identification of therapeutic targets to improve fibril formation and to enhance the positive cell signaling during tissue development, as well as to enhance the function of developed tissues. The outcome of this study will also provide insight into the folding and the self-association of fibrous protein in general and further the research of engineering collagen-based microscopic fibrils for biomedical applications. fibrils