Institute of Molecular Biology
Assistant Professor, Chemistry and Biochemistry
Ph.D. Johns Hopkins University
B.S. Oregon State University
Office: Willamette Hall Room 340A
Office Phone: 541-346-9002
Lab: Willamette Hall Room 340
Lab Phone: 541-346-9003
The overarching goal of the Harms lab is to understand the relationship between the biophysical properties of proteins and their evolution. Why do proteins with certain sequences and physical properties—out of a huge space of possibilities—occur? How do the physical properties of proteins shape their evolutionary trajectories? Which protein features are optimized by evolution, and which are determined by chance? How does a blind evolutionary process assemble complex features like ligand binding sites or allosteric regulation? Is protein evolution predictable or stochastic? To answer these (and other) questions, we take a synthetic approach, combining concepts and methodologies from classical biophysics and evolutionary biology. We employ advanced phylogenetics techniques (including ancestral protein resurrection), high-throughput experimental screens, and rigorous experimental/computational biophysical approaches to directly study the interplay of evolutionary and biophysical forces in generating both the complexity and diversity of natural proteins.
The S100 protein family as an evolutionary biophysical model
A powerful model system allows deep and nuanced studies that provide insights inaccessible in more complex systems: Drosophila for evolutionary developmental biology, ribonuclease H for protein folding, and—in our case—the S100 family for evolutionary biophysics. The S100s are small (~10 kDa) allosteric calcium binding proteins that ligate calcium and then recruit and regulate specific target proteins. They possess a number of properties that make them an excellent family for asking evolutionary biophysical questions.
- The S100s are functionally and biophysically diverse. Humans possess 21 family members that are involved in a wide variety of cellular processes including the stress response, cell motility, signaling, and tumor suppression. They are important for organ and tissue development, inflammation, and antimicrobial defense and have been implicated in autoimmune disease, cancer, and neurodegenerative disorders. This functional diversity is undergirded by biophysical diversity, including altered metal binding, protein target binding specificity, binding cooperativity, allostery, and oligomerization state. By studying how these core biophysical properties evolved in the S100s, we gain insight into how these properties evolve in other protein families.
- The S100s are experimentally and phylogenetically tractable. A key feature of a model system a match between what is asked and what can be studied experimentally. The S100s can be easily expressed/purified and are well behaved in solution, making them amenable for biophysical characterization. Further, the shared properties of the protein family mean that early experimental development for studies of a few family members lower the barrier for future studies of interesting evolutionary transitions across the protein family. They are also small enough that the entire protein sequence can be covered with Illumina paired-end reads, allowing high-throughput studies of mutations at any (or all) sites in the protein. Finally, they align well and possess enough phylogenetic signal to allow robust phylogenetic inference and high quality reconstruction of ancestral protein sequences.
- Current S100 projects. We are currently using S100 family members to ask how allosteric sites can evolve de novo. One family member acquired a new, an antagonistic binding site ~300 million years ago. How could a blind process assemble a site with multiple residues? Were there functionally neutral—or even deleterious—steps on the way? To what extent is the allostery optimized rather than a “natural” consequence of the protein architecture? We also have other projects in the pipeline looking at properties like the evolution of heterodimeric proteins from homodimeric ancestors, and the convergent evolution of peptide binding sites.
(pulled from pubmed)
(pulled from pubmed)