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

胶原蛋白是人体中含量最丰富的蛋白质，也是结缔组织的主要成分 并且与包括癌症，发育异常， 动脉粥样硬化和衰老。胶原蛋白分子功能的多样性与其显著的生物学特性密切相关。 胶原蛋白单体-三螺旋-形成不同超分子组装体的能力。然而， 胶原蛋白原纤维形成的结构和机制仍然知之甚少。缺乏这种 知识限制了我们对组织发育和功能所涉及的分子事件的理解， 阻碍了我们对胶原相关疾病病因的理解。 我们的长期研究目标是了解原纤维形成的机制及其对细胞生长的影响。 参与生物过程。纤维状胶原的纤维形成代表了最普遍的 胶原蛋白的自组装过程，是骨骼、皮肤和皮肤发育和功能的重要步骤， 和血管壁。功能性胶原原纤维的特征在于特定的轴向重复结构 67 nm，称为D周期。最近，我们开发了一种细菌表达系统， 重组三螺旋，命名为Col 108， 是由两种分子性质决定的 特定的残基和它们沿着三螺旋的特定位置;此外，我们提出胶原蛋白 突变通过破坏特定的相互作用而损害三螺旋的自组装， 结构层面的发展。当前提案的直接目标是：（1）确定具体的 Col 108自组装过程中的分子相互作用，2）以表征 Col 108的自组装和3）以产生形成原纤维的合成三螺旋肽。重大创新 的拟议工作来自于研究胶原蛋白三螺旋的自缔合能力， 在原纤维形成水平上表征致病突变的影响。拟议的工作将是 使用诱变方法、生物物理表征和肽合成的组合进行 化学.总的来说，拟议的工作将从根本上提高我们对分子生物学的理解。 参与胶原纤维形成的相互作用。这些知识将导致识别 改善原纤维形成和增强组织中的阳性细胞信号传导的治疗靶点 发育，以及增强发育组织的功能。这项研究的结果也将 提供了深入了解折叠和纤维蛋白质的自缔合一般和进一步的研究， 用于生物医学应用的基于胶原蛋白的微纤维工程。 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