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Principal Investigator: Michael Jonathan Harms
Organization: UNIVERSITY OF OREGON
Fiscal Year: 2024
Award: $364,885
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Acylation><Address><Amphibia><Amphibians><Animal Model><Animal Models and Related Studies><Animals><Binding><Binding Sites><Bio-Informatics><Biochemical><Biochemistry><Bioinformatics><Biologic Models><Biological Chemistry><Biological Models><Biology><Biophysics><Body Tissues><Brachydanio rerio><CAGB><CD14><CD14 gene><CGCB><Cell Communication and Signaling><Cell Signaling><Combining Site><Complex><Conflict><Conflict (Psychology)><Danio rerio><Depressed mood><Disease><Disorder><Drug Targeting><Evolution><Exhibits><Exposure to><GeneHomolog><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><Health><Homolog><Homolog of Drosophila TOLL><Homologous Gene><Homologue><Human><Human Biology><Immune><Immunes><Infection><Inflammation><Inflammatory><Innate Immunity><Intracellular Communication and Signaling><Investigation><LIAG><Lipopolysaccharides><MAC387><MRP14><Macromolecular Protein Complexes><Mammalia><Mammals><Measurement><Microbe><Model System><Modern Man><Modernization><Molecular Interaction><Multiprotein Complexes><Mutation><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Osteichthyes><Outcome><Pattern><Phylogenetic Analysis><Phylogenetics><Play><Process><Proteins><Reactive Site><Role><S100A9><S100A9 gene><Sampling><Shapes><Siderophilin><Signal Transduction><Signal Transduction Systems><Signaling><Site><Specificity><Sterility><Structure><Study models><TLR4><TLR4 gene><Testing><Tetrapoda><Time><Tissues><Toll Homologue><Transferrin><Vertebrate Animals><Vertebrates><Work><Zebra Danio><Zebra Fish><Zebrafish><antagonism><antagonist><biological signal transduction><biophysical analysis><biophysical foundation><biophysical principles><biophysical sciences><biophysical studies><bony fish><depressed><experiment><experimental research><experimental study><experiments><fascinate><genome mutation><in vivo><insight><interest><lens><lenses><member><microbial><model of animal><mutation scanning><mutation screening><preservation><pressure><protein complex><protein function><reconstruction><sadness><simulation><social role><sterile><tetrapods><toll-like receptor 4><vertebrata>