Molecular mechanisms of ARF family GTPases

ARF家族GTP酶的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要调节 GTP 酶 ARF 家族的成员在细胞信号传导中充当节点协调重要的细胞过程；包括膜运输、能量代谢、纤毛发生和细胞骨架。我首先研究了 ARF，后来研究了 ARF 样 (ARL) 蛋白 30 多年来，结合使用生物化学、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，重点关注它们的作用与纤毛和中心体相连，可以对其中五个子集进行更详细的机制研究该家族中的 30 个 GTPases。我们将使用基因组编辑来生成基因敲除的集合细胞系破译所研究蛋白质的信号传导。我们将使用经典蛋白质生物化学来纯化和发现这些途径中的新成分。我们俩都会学习这五种 GTP 酶在细胞中的功能，并与其体外生化研究相关酶学。我们将探索细胞信号传导串扰或更高级别排序的潜力，还为非典型 GTPases 开发新颖的单一作用，作为确定共享的手段或家庭内独特的机制。更好地理解这些系统将揭示对细胞生物学基本方面的新颖见解以及提供潜在目标改变人类疾病进程的干预措施；包括但不限于癌症、心脏病疾病、神经变性、纤毛病、视网膜变性和耳聋。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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.