IDENTIFICATION OF POLYGLUTAMINE EXPANDED SCA7-ASSOCIATED PROTEINS

聚谷氨酰胺扩增 SCA7 相关蛋白的鉴定

• 批准号: 7420691
• 负责人: PATRICK A GRANT
• 金额: $ 0.29万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7420691
• 关键词: DNA; chromatin; genes; histones; homopeptide; human; proteins; yeasts

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In eukaryotes, DNA exists in the context of chromatin, in which it is tightly wrapped around histone proteins and consequently highly compacted. This close interaction between DNA and histones presents a fundamental problem for processes such as transcription, replication, and DNA repair in which direct access to the DNA template is required by the proteins that carry out these processes. Many chromatin modifying complexes, such as histone acetyltransferases (HATs) have been shown to regulate chromatin accessibility by transferring different moieties, such as acetyl groups, to the tail regions of histone proteins. Acetylated histones are often associated with transcriptionally active chromatin. The yeast HAT complex SAGA (for Spt-Ada-Gcn5 Acetyltransferase) is a highly conserved complex that has been shown to preferentially acetylate histones H3 and H2B. Another HAT identified in yeast, the SLIK (SAGA-Like) complex, is highly related to SAGA. The two have been shown to have a number of shared components and functions, as well as certain unique proteins. Novel proteins have been identified in both SAGA and SLIK by mass spectrometry, including that encoded by an open reading frame of unknown function. This protein contains domains which are homologous to the human gene SCA7, which encodes a protein responsible for the neurodegenerative disorder, spinocerebellar ataxia type 7. The physiological role of the normal SCA7 protein is unknown. Furthermore, the normal human SCA7 gene, but not the diseased version, compliments loss of the yeast SCA7 gene. However the polyglutamine expanded SCA7 protein (60Q) assembles a SAGA complex, which is unable to acetylate a chromatin template. Silver stain analysis indicates association of at least one putative novel protein in this 60Q complex, which may contribute to disease pathogenesis. The identification of this subunit may have significant implications for the function of the human SCA7 protein in disease pathogenesis.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在真核生物中，DNA存在于染色质的环境中，在染色质中，DNA紧密地包裹在组蛋白周围，因此高度紧密。DNA和组蛋白之间的密切相互作用为转录、复制和DNA修复等过程提出了一个基本问题，在这些过程中，执行这些过程的蛋白质需要直接访问DNA模板。许多染色质修饰复合物，如组蛋白乙酰转移酶（hat），已被证明通过将不同的部分（如乙酰基）转移到组蛋白的尾部区域来调节染色质的可及性。乙酰化组蛋白通常与转录活性染色质相关。酵母HAT复合体SAGA（用于Spt-Ada-Gcn5乙酰转移酶）是一种高度保守的复合体，已被证明优先乙酰化组蛋白H3和H2B。在酵母中发现的另一个HAT， SLIK （SAGA- like）复合体，与SAGA高度相关。这两种基因有许多共同的成分和功能，以及某些独特的蛋白质。通过质谱分析，在SAGA和SLIK中都发现了新的蛋白质，包括由未知功能的开放阅读框编码的蛋白质。该蛋白含有与人类基因SCA7同源的结构域，该基因编码一种与神经退行性疾病脊髓小脑共济失调7型有关的蛋白质。正常的SCA7蛋白的生理作用尚不清楚。此外，正常的人类SCA7基因，而不是患病的版本，弥补了酵母SCA7基因的缺失。然而，聚谷氨酰胺扩增的SCA7蛋白（60Q）组装了一个SAGA复合体，该复合体不能使染色质模板乙酰化。银染色分析表明，在60Q复合体中至少存在一种推测的新蛋白，这可能与疾病发病机制有关。该亚基的鉴定可能对人类SCA7蛋白在疾病发病机制中的功能具有重要意义。