STRUCTURAL STUDIES OF SACSIN AND EDD UBIQUITIN LIGASE

SACSIN 和 EDD 泛素连接酶的结构研究

• 批准号: 8171521
• 负责人: Kalle B Gehring
• 金额: $ 2.85万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171521
• 关键词: Adult; Ataxia; Canada; Code; Computer Retrieval of Information on Scientific Projects Database; Data; Defect; Development; Disease; Family member; Funding; Genes; Germ Cells; Grant; High Prevalence; Home environment; Hyperplasia; Individual; Institution; Molecular; Mutation; Neurodegenerative Disorders; Phase; Proteins; Quebec; Research; Research Personnel; Resolution; Resources; Saints; Solutions; Source; Spastic; Sterility; Structure; Substrate Specificity; Tumor Suppressor Proteins; Ubiquitin-mediated Proteolysis Pathway; United States National Institutes of Health; early onset; improved; mRNA Differential Displays; protein function; research study; sacsin; tumor; ubiquitin ligase; ubiquitin-protein ligase

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. Autosomal recessive spastic ataxia of Charlevoix¿¿"Saguenay (SACS) is an early-onset neurodegenerative disease with high prevalence in the Charlevoix¿¿"Saguenay¿¿"Lac-Saint-Jean region of Quebec (Canada). The gene responsible for SACS codes for sacsin, a protein containing more than 4000 residues. In order to better understand the function of this protein and its relation to the disease, we initiated structural studies of individual domains of sacsin. We recently obtained crystals of HEPN and UBL domains of sacsin. Both crystals diffract to 2.8-2.9A at the home source, but no solution was found by molecular replacement using distantly related structures (below 30% identity). We plan to improve resolution of the diffraction data and find experimental phases using MAD experiments. The tumor suppressor hyperplastic discs protein (HYD), also known as EDD (E3 isolated by differential display) or UBR5, is a member of the family of HECT (homologous to E6-AP carboxyl terminus) E3 ubiquitin ligases, which target specific proteins for ubiquitin-mediated proteolysis. Mutations in EDD fail to properly terminate proliferation leading to tumors and also result in developmental abnormalities such as adult sterility due to germ cells defects. We crystallized HECT domain of EDD. The crystals diffract to 3.0A at the home source. No molecular replacement solution was found. We are going to use MAD experiment for experimental phasing and to improve resolution of the crystals. The structure will be important to study a substrate specificity of EDD.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。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。列出的机构是 对于中心，这是调查员的机构。 Autosomal recessive spastic ataxia of Charlevoix¿ ¿ "Saguenay (SACS) is an early-onset neurodegenerative disease with high prevalence in the Charlevoix¿¿"Saguenay¿ ¿ "Lac-Saint-Jean region of Quebec (Canada). The gene responsible for SACS codes for sacsin, a protein containing more than 4000 residuals. In order to better了解该蛋白质的功能及其与疾病的关系，我们对Sacsin的各个结构域进行了结构性研究，我们获得了SACSIN的HEPN和UBL域的晶体。实验。 肿瘤抑制剂增生盘蛋白（HYD），也称为EDD（通过差分显示）或UBR5分离，是Hect（与E6-AP羧基末端）E3泛素连接酶家族的成员，它靶向泛素蛋白介导的蛋白质蛋白质的特异性蛋白质。 EDD中的突变无法正确终止导致肿瘤的增殖，也导致发育异常，例如由于生殖细胞缺陷而导致的成年无菌性。我们结晶了EDD的Hect域。晶体衍射到家庭源的3.0a。未发现分子替代溶液。我们将使用MAD实验进行实验相相并改善晶体的分辨率。该结构对于研究EDD的底物特异性很重要。