分类: 生物学 >> 生物物理学 >> 生物物理、生物化学与分子生物学 提交时间: 2016-05-12
摘要: Protein disulfide-isomerase (PIN) was the first protein-folding catalyst to be characterized, half a century ago. It plays critical roles in a variety of physiological events by displaying oxidoreductase and redox-regulated chaperone activities. This review provides a brief history of the identification of PDI as both an enzyme and a molecular chaperone and of the recent advances in studies on the structure and dynamics of PDI, the substrate binding and release, and the cooperation with its partners to catalyze oxidative protein folding and maintain ER redox homeostasis. In this review, we highlight the structural features of PDI, including the high interdomain flexibility, the multiple binding sites, the two synergic active sites, and the redox-dependent conformational changes. (C) 2015 Elsevier Inc. All rights reserved.
分类: 生物学 >> 生物物理学 >> 基因表达调控与表观遗传学 提交时间: 2016-05-11
摘要: FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.