Defining the Effect of Mutations on Collagen Folding

定义突变对胶原蛋白折叠的影响

• 批准号: 7062658
• 负责人: MICHAEL A BRYAN
• 金额: $ 2.65万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7062658
• 关键词: alanine; arginine; autosomal dominant trait; bioenergetics; calorimetry; chemical kinetics; chemical models; circular dichroism; collagen; gene mutation; glycine; osteogenesis imperfecta; peptide structure; predoctoral investigator; protein folding; protein sequence; serine; structural biology; thermodynamics; triple helix

DESCRIPTION (provided by applicant): Type I collagen is an important protein in connective tissues such as bone. Collagen forms a trimer that is capable of self-association to form fibers. These fibers then become incorporated into bone during mineralization. Mutations in type I collagen lead to Osteogenesis Imperfecta (Ol) where there is defective bone formation. Mutations resulting in the substitution of one Gly residue within the repeating (Gly-Xaa- Yaa)n pattern of type I collagen triple helix are the major cause of Ol. Collagen folding in the presence of a mutation has been shown to be delayed. Our hypothesis is that this delay in folding is due to a pause at the mutation site leading to an intermediate state stable enough to have a significant impact on folding. Collagen model peptides will be used to study how type I collagen propagates through a glycine mutation in Ol using Circular Dichroism (CD) and Differential Scanning Calorimetry (DSC). This study aims to determine whether the effects of different Gly mutations on collagen folding can ultimately provide insight into the varying phenotypes observed in Ol patients.

描述（由申请人提供）：I 型胶原蛋白是结缔组织（例如骨骼）中的重要蛋白质。胶原蛋白形成能够自缔合形成纤维的三聚体。这些纤维随后在矿化过程中融入骨骼中。 I 型胶原蛋白突变会导致成骨不全 (Ol)，即骨形成有缺陷。导致 I 型胶原三螺旋重复 (Gly-Xaa-Yaa)n 模式内一个 Gly 残基取代的突变是 Ol 的主要原因。 已证明存在突变时胶原蛋白折叠会延迟。我们的假设是，折叠的这种延迟是由于突变位点的暂停导致足够稳定的中间状态，从而对折叠产生重大影响。胶原蛋白模型肽将用于利用圆二色性 (CD) 和差示扫描量热法 (DSC) 研究 I 型胶原蛋白如何通过 Ol 中的甘氨酸突变进行增殖。本研究旨在确定不同 Gly 突变对胶原蛋白折叠的影响是否最终可以深入了解在 Ol 患者中观察到的不同表型。