热休克因子1(HSF1)是一种主要的转录调节因子,可介导热休克蛋白伴侣的诱导,用于蛋白质组的质量控制(QC)和维持蛋白质稳态,作为响应压力的保护机制。在成功隔离后的过去三十年中,这一特定领域的研究急剧加速,克隆,和HSF1的表征。由HSF1协调的复杂的多蛋白复合物和转录激活是细胞QC机制内的基本过程。我们的主要重点是HSF1在衰老和神经退行性疾病(ND)中的调节和功能,这些疾病代表了蛋白质QC功能障碍的生理和病理状态。本章概述了HSF1的结构,功能,和健康细胞中的能量特性,同时解决了HSF1功能的恶化,即年龄依赖性和神经元特异性对ND的脆弱性。我们讨论了HSF1的结构域,重点是内在无序的区域,并注意到与ND相关的疾病蛋白通常在结构上无序,并且对衰老过程中可能发生的细胞环境变化非常敏感。我们提出了一个假设,即内在无序的蛋白质组的年龄依赖性变化可能为理解许多功能,结构,以及衰老过程中蛋白质和信号通路的组织变化-包括ND中HSF1的功能障碍和疾病蛋白质聚集体的积累。结构摘要简介:热休克因子1(HSF1)是一种主要的转录调节因子,可介导热休克蛋白伴侣的诱导,用于蛋白质组的质量控制(QC),作为对压力的细胞保护机制。有累积证据表明,这种QC机制与年龄相关的恶化有助于疾病的脆弱性。
目的:在此讨论HSF1的调节和功能,因为它们与衰老和神经退行性疾病(ND)中蛋白质质量控制的病理生理变化有关。
方法:我们概述了HSF1结构,功能,和健康细胞中的能量特性,同时解决了HSF1功能相对于年龄依赖性和神经元特异性对神经退行性疾病的脆弱性的恶化。
结果:我们研究了内在无序区域对HSF1功能的影响,并注意到与神经变性相关的蛋白质是天然非结构化的,并且对衰老过程中可能发生的细胞环境变化非常敏感。
结论:我们提出了一个假设,即内在无序的蛋白质组的年龄依赖性变化为理解许多功能,结构,和蛋白质的组织变化-包括神经退行性疾病中HSF1在衰老和疾病蛋白聚集体的出现中的功能障碍。
Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome and maintenance of proteostasis as a protective mechanism in response to stress. Research in this particular area has accelerated dramatically over the past three decades following successful isolation, cloning, and characterization of HSF1. The intricate multi-protein complexes and transcriptional activation orchestrated by HSF1 are fundamental processes within the cellular QC machinery. Our primary focus is on the regulation and function of HSF1 in aging and neurodegenerative diseases (ND) which represent physiological and pathological states of dysfunction in protein QC. This chapter presents an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function viz-à-viz age-dependent and neuron-specific vulnerability to ND. We discuss the structural domains of HSF1 with emphasis on the intrinsically disordered regions and note that disease proteins associated with ND are often structurally disordered and exquisitely sensitive to changes in cellular environment as may occur during aging. We propose a hypothesis that age-dependent changes of the intrinsically disordered proteome likely hold answers to understand many of the functional, structural, and organizational changes of proteins and signaling pathways in aging - dysfunction of HSF1 and accumulation of disease protein aggregates in ND included.Structured AbstractsIntroduction: Heat shock factor 1 (HSF1) is a master transcription regulator that mediates the induction of heat shock protein chaperones for quality control (QC) of the proteome as a cyto-protective mechanism in response to stress. There is cumulative evidence of age-related deterioration of this QC mechanism that contributes to disease vulnerability.
OBJECTIVE: Herein we discuss the regulation and function of HSF1 as they relate to the pathophysiological changes of protein quality control in aging and neurodegenerative diseases (ND).
METHODS: We present an overview of HSF1 structural, functional, and energetic properties in healthy cells while addressing the deterioration of HSF1 function vis-à-vis age-dependent and neuron-specific vulnerability to neurodegenerative diseases.
RESULTS: We examine the impact of intrinsically disordered regions on the function of HSF1 and note that proteins associated with neurodegeneration are natively unstructured and exquisitely sensitive to changes in cellular environment as may occur during aging.
CONCLUSIONS: We put forth a hypothesis that age-dependent changes of the intrinsically disordered proteome hold answers to understanding many of the functional, structural, and organizational changes of proteins - dysfunction of HSF1 in aging and appearance of disease protein aggregates in neurodegenerative diseases included.