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Evolution of new protein function in the multi-protein, multi-functional Toll-like receptor 4 complex

多蛋白、多功能Toll样受体4复合物中新蛋白功能的进化

基本信息

批准号：
10625469
负责人：
Michael Jonathan Harms
金额：
$ 36.49万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625469
关键词：
Acylation Address Amphibia Animal Model Animals Binding Binding Sites Biochemical Biochemistry Bioinformatics Biological Models Biology Biophysics CD14 gene Complex Conflict (Psychology)Depressed mood Disease Drug Targeting Evolution Exhibits Exposure to Genetic Goals Health Homologous Gene Human Human Biology Immune Infection Inflammation Inflammatory Investigation Lipopolysaccharides Mammals Measurement Microbe Modernization Multiprotein Complexes Mutation Natural Immunity Osteichthyes Outcome Pattern Phylogenetic Analysis Play Process Proteins Role S100A9 gene Sampling Shapes Signal Transduction Site Specificity Sterility Structure Study models TLR4 gene Testing Tetrapoda Time Tissues Transferrin Vertebrates Work Zebrafish antagonist biophysical analysis experimental study fascinate in vivo insight interest lens member microbial mutation screening preservation pressure protein complex protein function reconstruction simulation

项目摘要

SUMMARY Understanding the evolution of protein function is a central goal in evolutionary biochemistry. Most mechanistic work on this problem has focused on single proteins with single functions; however, proteins often work as members of multi-functional, multi-protein complexes. How can evolution optimize one protein function without breaking another? How are new proteins integrated into multi-protein complexes? Answering these and other questions requires mechanistic studies of the natural evolution of multi-functional, multi-protein complexes. To answer these questions, we propose studying the evolution of Toll-like receptor 4 (TLR4)—a multi-protein, multi-functional protein complex found in vertebrate animals. This complex is central to how animals respond to both infection and tissue damage. It is the subject of intense interest, both from the perspective a basic biology and as a drug target for inflammatory disorders. The complex evolved in serial over hundreds of millions of years. In this work, we will pose—and answer—three questions: 1) How did the ability of the complex to recognize pro- inflammatory signals change over the last 300 million years? 2) What were the evolutionary forces and processes that led to these functional changes? 3) How did a completely new protein evolve in the ancestor of land animals and become integrated into the complex? To answer these questions, we will employ a combination of phylogenetic analysis, ancestral sequence reconstruction, high-throughput protein characterization, biochemical/biophysical studies, careful functional characterization, and in vivo experiments in zebrafish. This work will provide unprecedented understanding of the mechanisms—both biochemical and evolutionary— that lead to new function in multi-functional protein complexes. By specifically studying the evolutionary process that led to the human TLR4 complex, this work will also provide a lens through which we can interpret animal model studies of innate immunity and apply their findings to human biology. And, finally, an evolutionary approach is a powerful means to dissect how proteins work. Our results will provide deep insight into how this important protein complex functions and can be manipulated to achieve better human health outcomes.

总结