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

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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