STRUCTURAL STUDIES OF THE LOWE SYNDROME PROTEIN OCRL

Lowe 综合征蛋白质 OCRL 的结构研究

• 批准号: 7955098
• 负责人: Pietro De Camilli
• 金额: $ 0.01万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955098
• 关键词: American Society of Hematology; Benign congenital hypotonia; Biochemical; Biological Process; Boxing; C-terminal; Cell physiology; Clathrin; Computer Retrieval of Information on Scientific Projects Database; Cytosol; Data Set; Disease; Enzymes; Family; Fanconi Syndrome; Funding; Grant; Institution; Intracellular Second Messenger; Kidney; Link; Membrane; Mental Retardation; Metabolism; Mutation; Names; Oculocerebrorenal Syndrome; Phosphatidylinositols; Play; Property; Proteins; Research; Research Personnel; Resources; Role; Second Messenger Systems; Source; Structure; United States National Institutes of Health; congenital cataract; human disease; member; novel; rho GTPase-activating protein; structural biology

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. It is well known that phophoinositides (PIs) play a pivotal role in almost all aspects of cell physiology both as precursors of intracellular second messengers and as regulators of membrane-cytosol interfaces. Phosphoinositide metabolism is tightly regulated by a large number of phosphoinositide metabolizing enzymes, and mutations of several such enzymes are responsible for human disease. Mutations in OCRL (also referred to as INPP5E) cause OculoCerebroRenal Syndrome of Lowe, an X-linked disorder characterized by congenital cataracts, mental retardation, neonatal hypotonia, and renal Fanconi syndrome. Despite many studies of the biochemical properties and cellular functions of OCRL, structural information on this multi-domain enzyme, which is essential for our understanding of its biological functions, is still limited. We successfully crystallized the C-terminal part of OCRL, which contains a novel domain named the ASH domain and a RhoGAP like domain. With the help by the NE-CAT team, we collected an anomalous diffraction data set and solved the structure of the C-terminal part of OCRL. Our crystallographic studies of the COOH-terminal region of OCRL reveal the first structure of a member of the newly defined ASH domain family. Our structure reveals with an unusual clathrin box protruding from a large loop inside the RhoGAP-like domain. Moreover, our structural studies elucidate a potential link between OCRL mutations and the phenotypic manifestations of Lowe syndrome.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 众所周知，磷酸肌醇（PI）在细胞生理学的几乎所有方面都发挥着关键作用，既作为细胞内第二信使的前体，又作为膜-细胞质界面的调节剂。 磷酸肌醇代谢受到大量磷酸肌醇代谢酶的严格调控，其中几种此类酶的突变是导致人类疾病的原因。 OCRL（也称为 INPP5E）突变会导致 Lowe 眼脑肾综合征，这是一种 X 连锁疾病，其特征为先天性白内障、智力低下、新生儿肌张力低下和肾范科尼综合征。尽管对 OCRL 的生化特性和细胞功能进行了许多研究，但这种多域酶的结构信息对于我们理解其生物学功能至关重要，但仍然有限。我们成功结晶了 OCRL 的 C 端部分，其中包含一个名为 ASH 结构域的新结构域和一个类似 RhoGAP 的结构域。在NE-CAT团队的帮助下，我们收集了异常衍射数据集并解析了OCRL C端部分的结构。我们对 OCRL COOH 末端区域的晶体学研究揭示了新定义的 ASH 结构域家族成员的第一个结构。我们的结构揭示了一个不寻常的网格蛋白盒从 RhoGAP 样结构域内的大环突出。此外，我们的结构研究阐明了 OCRL 突变与 Lowe 综合征表型表现之间的潜在联系。