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.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子弹和调查员（PI）可能已经从其他NIH来源获得了主要资金，因此可以在其他清晰的条目中代表。列出的机构适用于该中心，这不一定是调查员的机构。在真核生物中，DNA存在于染色质的背景下，其中将其紧密包裹在组蛋白蛋白上并因此高度压实。 DNA和组蛋白之间的这种紧密相互作用提出了转录，复制和DNA修复过程的基本问题，在这种过程中，执行这些过程的蛋白需要直接访问DNA模板。许多染色质修饰复合物（例如组蛋白乙酰转移酶（HAT））已证明通过将不同的部分（例如乙酰基）转移到组蛋白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有关。酵母帽复合物传奇（对于SPT-ADA-GCN5乙酰转移酶）是一种高度保守的络合物，已显示出优先乙酰化组蛋白H3和H2B。在酵母中鉴定出的另一个帽子是Slik（Saga-like）综合体，与传奇高度相关。两者已被证明具有许多共享组件和功能以及某些独特的蛋白质。新型蛋白质已通过质谱法在传奇和Slik中都鉴定出来，包括由未知功能的开放阅读框架编码的蛋白质。该蛋白质包含与人类基因SCA7同源的结构域，该结构域编码了负责神经退行性疾病的蛋白质，脊髓脑性共济失调7型。正常SCA7蛋白的生理作用尚不清楚。此外，正常的人类SCA7基因，但不是患病的基因，这补充了酵母Sca7基因的丧失。然而，聚谷氨酰胺扩展了SCA7蛋白（60q），组装了一种传奇络合物，该复合物无法乙酰化染色质模板。银色染色分析表明，在这种60Q复合物中，至少一种假定的新型蛋白质的关联，这可能有助于疾病发病机理。该亚基的鉴定可能对人SCA7蛋白在疾病发病机理中的功能具有重要意义。