Structural Significance of Point Mutations within the Human hsp60 Chaperonin

 描述(申请人提供)：神经退行性疾病包括多种情况，包括神经功能的进行性衰退。遗传性痉挛截瘫(HSP)和MIT-CHAP-60属于一个较大的遗传性疾病组，其特征是精神运动发育迟缓、非自愿眼球运动(眼球震颤)、肌肉张力低下(低张力)和虚弱，以及可能导致行走能力受损的明显僵硬(痉挛)。HSP和MIT-CHAP-60都与编码人类热休克蛋白60(HSP60)的HSPD1基因点突变有关，HSP60是一种帮助蛋白质折叠的基本蛋白质复合体，称为伴侣蛋白。拟议研究项目的主要目标是确定和描述导致这两种疾病的点突变所导致的结构变化。到目前为止，PDB数据库中还没有人类热休克蛋白60(也称为CPN 60和HSP60)的结构。因此，我们对HSP60活性降低导致这些疾病的发生发展没有详细的了解。我们的工作假说是，Hsp60/10伴侣系统的蛋白质折叠路径被每个点突变通过14亚基复合体的不稳定而改变，这反过来又降低了整体伴侣的活性。一般来说，伴侣活性对所有活细胞都是至关重要的，而在这些细胞中，伴侣活性的缺失也是致命的。这些伴随蛋白缺陷的疾病会导致伴随蛋白仍有轻微的活性，但活性不足，不足以形成正常的表型。拟议项目的总体目标是确定遗传性痉挛截瘫和MIT-CHAP-60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.