Molecular mechanisms of ARF family GTPases

ARF家族GTP酶的分子机制

• 批准号: 10675436
• 负责人: Richard A Kahn
• 金额: $ 50.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675436
• 关键词: Arl proteins; Biochemical; Biological; Cell Line; Cell physiology; Cells; Cellular biology; Centrosome; Cilia; Collection; Cytoskeleton; Energy Metabolism; Enzymatic Biochemistry; Family; Functional disorder; Genetic; Guanosine Triphosphate Phosphohydrolases; Heart Diseases; Human; In Vitro; Intervention; Knock-out; Link; Malignant Neoplasms; Membrane Protein Traffic; Molecular; Nerve Degeneration; Pathway interactions; Phylogenetic Analysis; Protein Biochemistry; Regulation; Retinal Degeneration; Signal Transduction; Signaling Protein; System; ciliopathy; cilium biogenesis; deafness; genome editing; human disease; insight; member; novel

Project Summary/Abstract Members of the ARF family of regulatory GTPases function as nodes in cell signaling to coordinate essential cell processes; including membrane traffic, energy metabolism, ciliogenesis, and the cytoskeleton. I have studied first ARF and later ARF-like (ARL) proteins for over 30 years, using a combination of biochemical, cell and molecular biological, genetic, and phylogenetic approaches and propose to continue these studies with a focus on their actions linked to cilia and centrosomes to allow more detailed mechanistic studies of a subset of five of the 30 GTPases in this family. We will use genome editing to generate a collection of knockout cell lines to decipher signaling by the proteins under study. And we will use classical protein biochemistry to purify and discover novel components in these pathways. We will both study functions of each of these five GTPases in cells, and link to in vitro biochemical studies of their enzymology. We will explore the potential for cross-talk or higher level ordering of cell signaling, and also develop novel, single actions for atypical GTPases as a means of determining shared or unique mechanisms within the family. A better understanding of these systems will reveal novel insights into fundamental aspects of cell biology as well as providing potential targets for intervention to alter the course of human diseases; including but not limited to cancer, heart disease, neurodegeneration, ciliopathies, retinal degeneration, and deafness.

项目摘要/摘要 调节GTPases的ARF家族的成员在细胞信号中起淋巴结功能 协调必需的细胞过程；包括膜交通，能源代谢， 纤毛生成和细胞骨架。我已经研究了第一个ARF，然后研究了类似ARF的（ARL）蛋白 30年来，使用生化，细胞和分子生物学，遗传和 系统发育方法并建议继续这些研究，重点是 与纤毛和中心体相关联，以允许对五个子集的更详细的机械研究 这个家庭中的30个GTPase。我们将使用基因组编辑来产生淘汰赛的集合 细胞系通过研究的蛋白质解密信号传导。我们将使用古典蛋白 在这些途径中净化和发现新成分的生物化学。我们都会研究 细胞中这五个GTPases中的每一个的功能，并与其体外生化研究联系起来 酶学。我们将探索细胞信号传导的串扰或更高级别排序的潜力， 并为非典型GTPases开发出新颖的单一动作，以确定共享 或家庭中的独特机制。对这些系统的更好理解将揭示 对细胞生物学基本方面的新颖见解，并为 干预以改变人类疾病的进程；包括但不限于癌症，心脏 疾病，神经变性，纤毛病，视网膜变性和耳聋。

项目成果

Mistakes in translation: Reflections on mechanism.

• DOI: 10.1371/journal.pone.0180566
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Liu Y;Sharp JS;Do DH;Kahn RA;Schwalbe H;Buhr F;Prestegard JH
• 通讯作者: Prestegard JH

A novel homozygous ARL13B variant in patients with Joubert syndrome impairs its guanine nucleotide-exchange factor activity.

Joubert 综合征患者体内的一种新型纯合 ARL13B 变异会损害其鸟嘌呤核苷酸交换因子活性。

• DOI: 10.1038/s41431-017-0031-0
• 发表时间: 2017
• 期刊: European journal of human genetics : EJHG
• 作者: Rafiullah,Rafiullah;Long,AlyssaB;Ivanova,AnnaA;Ali,Hazrat;Berkel,Simone;Mustafa,Ghulam;Paramasivam,Nagarajan;Schlesner,Matthias;Wiemann,Stefan;Wade,RebeccaC;Bolthauser,Eugen;Blum,Martin;Kahn,RichardA;Caspary,Tamara;Rappold,
• 通讯作者: Rappold,

Compositional complexity of rods and rings.

• DOI: 10.1091/mbc.e18-05-0274
• 发表时间: 2018-09-15
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Schiavon CR;Griffin ME;Pirozzi M;Parashuraman R;Zhou W;Jinnah HA;Reines D;Kahn RA
• 通讯作者: Kahn RA

Phylogenetic profiling and cellular analyses of ARL16 reveal roles in traffic of IFT140 and INPP5E.

• DOI: 10.1091/mbc.e21-10-0509-t
• 发表时间: 2022-04-01
• 期刊: MOLECULAR BIOLOGY OF THE CELL
• 影响因子: 3.3
• 作者: Dewees, Skylar, I;Vargova, Romana;Hardin, Katherine R.;Turn, Rachel E.;Devi, Saroja;Linnert, Joshua;Wolfrum, Uwe;Caspary, Tamara;Elias, Marek;Kahn, Richard A.
• 通讯作者: Kahn, Richard A.

A Eukaryote-Wide Perspective on the Diversity and Evolution of the ARF GTPase Protein Family.

• DOI: 10.1093/gbe/evab157
• 发表时间: 2021-08-03
• 期刊: Genome biology and evolution
• 影响因子: 3.3
• 作者: Vargová R;Wideman JG;Derelle R;Klimeš V;Kahn RA;Dacks JB;Eliáš M
• 通讯作者: Eliáš M