Molecular Basis of Osteogenesis Imperfecta

超出所提供的空间。成骨不全症（OI）通常是由编码I型前胶原蛋白（骨的主要结构蛋白）链的两个基因COL1A1和COL1A2突变引起的。最常见的突变导致在两条链的三螺旋结构域中替换甘氨酸残基。剪接位点突变是常见的，这两种类型的突变通常导致分子的组装具有中断的三螺旋。根据破坏的位置和性质，这些分子通常难以通过分泌途径，因为它们无法通过质量控制检查点。另一类不太常见的突变，即破坏c端前肽中任意一条链的序列，也会干扰分子组装，但发生在链链识别之前或过程中。与改变三螺旋序列的突变相反，c端突变通过激活结合异常蛋白的伴侣蛋白（如BiP (GRP78)）的合成，在细胞中引发一系列不同的反应。在某些情况下，这些蛋白质非常不稳定，并且可能被蛋白酶体或rer驻留蛋白酶迅速降解。我们在这个应用程序中的目标是确定改变proa1(1)和proa2(I)链序列的其他C-前肽突变，表征它们对分子组装的影响，检查它们在细胞中的分布，并确定它们被降解和随后降解的机制。我们将分析一组选定的细胞株突变，然后检查对分子组装在他们的家庭细胞的影响。然后，我们将用添加抗原表位的载体表达c端前肽，这些抗原表位可以用可用的抗体识别，以检查它们的命运、在细胞中的分布以及在有限的细胞环境中与正常链相互作用的能力。最后，我们将确定这些蛋白质被识别和破坏的位点和方法。这些研究应该提高我们对这种疾病和细胞中异常蛋白被识别的机制的理解。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIDED. Osteogenesis imperfecta (OI) usually results from mutations in the two genes, COL1A1 and COL1A2 that encode the chains of type I procollagen, the major structural protein of bone. The most common mutations result in substitutions for glycine residues within the triple helical domain of both chains. Splice site mutations are common and both these classes of mutations often lead to the assembly of molecules with disrupted triple helices. Depending on the location and nature of the disruption, the molecules often have difficulty navigating the secretory pathway because of failure to pass muster in the quality control checkpoints. A much less common class of mutations, those that disrupt the sequences of either chain in the C-terminal propeptide, also interfere with molecular assembly, but prior to or during chain-chain recognition. In contrast to mutations that alter the triple helical sequences, the C-terminal mutations initiate a different array of responses in the cell by activating the synthesis of chaperones, like BiP (GRP78) that bind the abnormal protein. In some instances these proteins are extremely unstable and rapidly degraded, possiblyby proteasomes or by RER-resident proteases. Our aims in this application are to identify additional C- propeptide mutations that alter sequences in both the proa1(1) and proa2(I) chains, to characterize their effects on molecular assembly, examine their distribution in the cell and identify the mechanisms bywhich they are targeted for degradation and then degraded. We will analyze a set of selected cell strains for mutations and then examine the effects on molecular assembly in their home cells. We will then express the C-terminal propeptide with vectors that add antigenic epitopes that are identifiable with available antibodies to examinetheir fate, distribution in the cell, and ability to interact with normal chains in a restricted cellular context. Finally, we will identify the site and means by which these proteins are recognized and then destroyed. These studies should improve our understanding of this disorder and mechanisms by which abnormal proteins are recognized in cells. PERFORMANCE SITE ========================================Section End===========================================