Structural Significance of Point Mutations within the Human hsp60 Chaperonin

 描述（由申请人提供）：神经退行性疾病包括多种病症，包括神经功能的进行性衰退。该组包括遗传性痉挛性截瘫（HSP）和mit-pneumatic-60，属于一组较大的遗传性疾病，其特征为精神发育迟缓、不自主眼球运动（眼球震颤）、低肌张力（张力减退）和虚弱，以及可能导致行走能力受损的突出僵硬（痉挛）。HSP和mit-CRP-60都与编码人热休克蛋白60（hsp 60）的HSPD 1基因中的相应点突变有关，热休克蛋白60是一种辅助蛋白质折叠的必需蛋白质复合物，称为伴侣蛋白。拟议研究项目的主要目标是确定和表征导致这两种疾病的点突变所导致的结构变化。 迄今为止，PDB数据库中还没有人热休克蛋白60（也称为CPN 60和hsp 60）的结构。因此，我们对导致这些疾病发展的hsp 60活性降低没有详细的了解。我们的工作假设是，hsp 60/10伴侣蛋白系统的蛋白质折叠途径被改变的每个点突变，通过14亚基复合物的不稳定，从而降低整体伴侣蛋白的活性。一般来说，伴侣蛋白活性对所有活细胞都是至关重要的，其中所述活性的损失是致命的。这些有缺陷的伴侣蛋白疾病导致其中伴侣蛋白仍具有轻微活性但活性不足以允许正常表型的病症。该项目的首要目标是确定遗传性痉挛性截瘫和MIT-P60疾病的分子基础。

 DESCRIPTION (provided by applicant): Neurodegenerative disorders include a large variety of conditions that include a progressive decay of neural function. Included in this group are hereditary spastic paraplegia (HSP) and mit-CHAP-60 which belong to a larger group of inherited conditions characterized by psychomotor developmental delay, involuntary eye movement (nystagmus), low muscle tone (hypotonia) and weakness, and prominent stiffness (spasticity) that may lead to impaired ability to walk. Both HSP and mit-CHAP-60 have been linked to respective point mutations in the HSPD1 gene that encodes the human heat shock protein 60 (hsp60), an essential protein complex that assists in protein folding termed a chaperonin. The main goal of the proposed research project is to identify and characterize structural changes that result from the point mutations that lead to these two diseases. To date, there has not been a structure deposited in the PDB databank for the human heat shock protein 60 (also called CPN 60 and hsp60). Therefore, we do not have a detailed understanding for the decreased activity of hsp60 that leads to the development of these diseases. Our working hypothesis is that the protein folding pathway of the hsp60/10 chaperonin system is altered by the each point mutation through a destabilization of the 14 subunit complex that in turn lowers overall chaperonin activity. Chaperonin activity in general is critical to all living cells where aloss in said activity is lethal. These defective chaperonin diseases result in a condition where the chaperonin is still slightly active but not sufficiently active to allow for a normal phenotype. Th overarching goal of the proposed project is to define the molecular basis for hereditary spastic paraplegia and Mit-CHAP- 60 disease.