The Muir lab investigates the physiochemical basis of protein function in complex systems of biomedical interest. We study protein function using an integration of synthetic organic and physical chemistry tools in combination with those of molecular genetics. Driven by a series of biological questions, we have developed general chemical biology approaches that allow the covalent structure of proteins to be manipulated with a similar level of control to those possible with smaller organic molecules. These technologies, which can be applied both in vitro and in vivo, allow the insertion of unnatural amino acids, posttranslational modifications and isotopic probes site-specifically anywhere into proteins. Our innovative methods are now used by numerous laboratories worldwide to address a large number of biomedical questions. A summary of ongoing work in the Muir group is provided below:

Chromatin
The eukaryotic genome is organized as a DNA-protein complex called chromatin. This architecture enables dynamic compaction of DNA within the confined space of the nucleus, and facilitates access to desired genomic loci through post-translational modification of scaffold proteins, histones. In the Muir lab, we use synthetic ‘designer’ chromatin to investigate the molecular basis of how histone modifications control DNA-templated processes and how aberrant chromatin signaling pathways contribute to pathologies.

Oncohistones
Mutations in histone proteins, such as H3K27M, H3G34R/V, and H3K36M, have been associated with cancers. Recently, we and other researchers have uncovered thousands more cancer-associated histone mutations which remain largely uncharacterized. Using a cross-disciplinary, chemical biology approach, our lab seeks to dissect the molecular mechanisms by which these so-called “oncohistones” contribute to the development and progression of cancer.

Inteines
Inteins, found in a variety of unicellular organisms, are polypeptide sequences that are able to excise themselves from flanking protein regions, exteins, and to ligate the exteins together. While the biological function of inteins remains a mystery, this class of proteins has found widespread use in the fields of chemical and cell biology. Recognizing the unique intein splicing reaction as a platform for the development of chemical biological tools, the Muir Lab aims to characterize the precise biochemical requirements for intein splicing and to engineer inteins with enhanced properties for the development of novel intein-based technologies.

Agr
Bacteria communicate through small-molecule signals. A commensal pathogen, Staphylococcus aureus, secretes a peptide pheromone, AIP, which acts as an extracellular indicator of the population density and coordinates its virulence response. Production and sensing of AIP involves four Agr, accessory gene regulator, proteins. The Muir lab uses highly purified recombinant or synthetic components to reconstitute these processes and to investigate how each Agr protein carries out its function at the molecular level.

The field of epigenetics has exploded over the last two decades revealing an astonishing level of complexity in the way genetic information is stored and accessed in eukaryotes. This expansion of knowledge, very much ongoing, has been made possible by the availability of ever more sensitive and precise molecular tools, including those grounded in the fields of peptide and protein chemistry.

In this presentation, I will discuss the development of new opto-chemical genetic approaches designed to explore spatiotemporal aspects of epigenetic regulation. These methods are helping to expose the remarkable nuances, and vulnerabilities, of epigenetic control mechanisms, providing insights into how these processes become corrupted in disease settings.