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Signal Integration from Membranes to the Actin Cytoskeleton

从膜到肌动蛋白细胞骨架的信号整合

基本信息

批准号：
10623679
负责人：
Baoyu Chen
金额：
$ 40.65万
依托单位：
IOWA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623679
关键词：
Actins Address Binding Binding Sites Biochemistry Biology Cell membrane Collaborations Complex Cryoelectron Microscopy Cytoskeleton DNA Sequence Alteration Defect Development Disease Eukaryotic Cell Fluorescence Fluorescence Microscopy Foundations Guanosine Triphosphate Phosphohydrolases Human Pathology Immune Immunologic Deficiency Syndromes Individual Infection Knowledge Laboratories Ligands Link Malignant Neoplasms Mass Spectrum Analysis Mediating Membrane Membrane Proteins Monomeric GTP-Binding Proteins Morphogenesis Mutation Names Neoplasm Metastasis Neurodevelopmental Disorder Neurons Oxidation-Reduction Parasitic infection Patients Phosphatidylinositols Play Polymers Process Protein Engineering Protein Family Proteins Regulation Research Role Series Signal Transduction Syndrome Therapeutic Vesicle WAVE protein Wiskott-Aldrich Syndrome Work axon guidance cell motility experimental study field study human disease immune activation interest novel particle pathogen polymerization receptor single molecule trafficking vasodilator-stimulated phosphoprotein

项目摘要

My laboratory has a long-term interest in understanding the basic mechanisms underlying actin cytoskeleton regulation and how these mechanisms drive fundamental processes such as cell migration, vesicle trafficking, immune cell activation, and neuron morphogenesis. We are particularly interested in solving the regulation mechanisms of the Wiskott-Aldrich Syndrome Protein (WASP) family proteins. These proteins play a central role in linking membrane signals to the Arp2/3-mediated actin polymerization throughout eukaryotic cells. Ge- netic mutation or misregulation of these proteins is heavily involved in human diseases, including various neu- rodevelopmental disorders, immune syndromes, pathogen infections, and cancer. Despite their importance, the regulation mechanisms of most WASP-family proteins are poorly understood, posing a large barrier to un- derstanding their roles in biology and human pathology and identifying new avenues of treating related dis- eases. Our recent studies have made a series of pivotal contributions to the understanding of the WASP-family protein WAVE and its role in disease. WAVE is incorporated in a large protein assembly named the WAVE Regulatory Complex (WRC), which is essential to polymerizing actin at the plasma membrane. We have deter- mined how WRC is activated by two distinct small GTPases, Rac1 and Arf, how disease-related mutations dis- rupt WRC activation, and how WRC interacts with various ligands, including the neuronal receptor HPO-30, the redox regulator p47phox, and the actin regulator Ena/VASP/UNC-34. In the next five years, we will continue to move the field vertically by addressing a series of new, important questions about WAVE regulation. In parallel, we will start exploring the mechanisms of two other WASP-family proteins, WHAMM and JMY, for which very little is known mechanistically despite their essential roles in regulating actin assembly at endomembranes. We will combine protein engineering, quantitative biochemistry and mass spectrometry, single molecule fluores- cence microscopy, and single particle cryogenic electron microscopy (cryo-EM) to determine how WRC is acti- vated by Arf binding, how distinct Arf and Rac1 binding sites establish cooperativity, and how WRC interacts with several novel ligands important to neuron morphogenesis, axon guidance, and parasite infection. In addi- tion to dissecting mechanisms of individual ligands, we will establish membrane-based single-molecule fluores- cence experiments to determine the mechanisms by which multiple ligands, including inositol phospholipids, GTPases, and membrane proteins, cooperatively activate the WRC in a context closely resembling cell mem- branes. Furthermore, we will determine how WHAMM and JMY are regulated by binding to various ligands. Our work will provide a comprehensive mechanistic framework for understanding WASP family protein regula- tion. This knowledge will be broadly useful to different fields studying actin-related processes. In collaboration with various biologists and clinicians, our work will reveal how mutations in WASP-family proteins derived from patients disrupt function and provide new ideas and targets for the development of novel intervening agents.

我的实验室对了解肌动蛋白细胞骨架的基本机制有着长期的兴趣

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genetics of mirror movements identifies a multifunctional complex required for Netrin-1 guidance and lateralization of motor control.

DOI：
10.1126/sciadv.add5501
发表时间：
2023-05-12
期刊：
Science advances
影响因子：
13.6
作者：
通讯作者：

A two-step actin polymerization mechanism drives dendrite branching.

DOI：
10.1186/s13064-021-00154-0
发表时间：
2021-07-19
期刊：
Neural development
影响因子：
3.6
作者：
Shi R;Kramer DA;Chen B;Shen K
通讯作者：
Shen K

WAVE regulatory complex.

DOI：
10.1016/j.cub.2021.01.086
发表时间：
2021-05-24
期刊：
Current biology : CB
影响因子：
0
作者：
Rottner K;Stradal TEB;Chen B
通讯作者：
Chen B

Structural basis for Retriever-SNX17 assembly and endosomal sorting.

Retriever-SNX17 组装和内体分选的结构基础。

DOI：
10.1101/2024.03.12.584676
发表时间：
2024
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Singla,Amika;Boesch,DanielJ;JoyceFung,HoYee;Ngoka,Chigozie;Enriquez,AveryS;Song,Ran;Kramer,DanielA;Han,Yan;Juneja,Puneet;Billadeau,DanielD;Bai,Xiaochen;Chen,Zhe;Turer,EmreE;Burstein,Ezra;Chen,Baoyu
通讯作者：
Chen,Baoyu

Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase.