Elizabeth M. Nolan
Metalloproteins in Health and Disease
Research in the Nolan Lab lies at the interface of chemistry and biology with current focus on metalloproteins and peptides involved in host/producer immunity, antibacterial action, or neurodegeneration.
The innate immune system provides plants and mammals with non-specific and front-line defense mechanisms following invasion by microbial pathogens. In broad terms, our initiatives in this area address the structures, reaction mechanisms, and physiological functions of putative metalloproteins and peptides that are components of the mammalian innate immune response. Our aim is to understand how and why certain broad-range antimicrobial peptides co-exist with and/or utilize d-block metal ion stores. Ultimately, these studies will provide new insights into metal ion physiology, host/pathogen interactions and microbial pathogenesis, and may guide the design of new small-molecule antimicrobial agents.
Many species of Gram-negative bacteria biosynthesize and posttranslationally modify ribosomal peptides that exhibit potent antimicrobial activity. The producer organism must be immune to the antibiotic it biosynthesizes and exports; in some cases, immunity peptides provide protection. Often, the mechanisms of action of these peptides are unclear. We seek to decipher how immunity peptides, encoded by gene clusters responsible for the biosynthesis of antibiotics that utilize metal ion transporters to enter target bacterial cells, protect the producer organism. We also aim to employ the enzymes responsible for posttranslational modification of such ribosomal peptide scaffolds in the chemoenzymatic synthesis of novel small-molecule and peptide-based antibiotics directed to Gram-negative strains.
Metalloproteins and peptides such as superoxide dismutase, metallothionein, and tyrosine hydroxylase play critical roles in neurobiology. Failures of metal ion homeostasis and metalloprotein misfolding have been correlated to many neurodegenerative diseases. For instance, approximately 100 single point mutations in CuZn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral schlerosis (ALS), a genetic disease that affects motor neurons. We are interested in ascertaining how a neuronal cell transports, processes and attempts to clear SOD1 point mutants. We will interrogate a putative adaptor function of a zinc-containing protein that would allow transport of mSOD1 along the microtubule network. Correlations of mSOD1 trafficking with disease prognosis should provide new insights into the pathophysiology of familial ALS and protein aggregation, which is a pathological hallmark of neurodegenerative diseases.
Our experimental approach blends the techniques of inorganic and organic chemistries, biochemistry, enzymology, and cell biology. Students and post-doctoral researchers will have the opportunity to gain expertise in synthesis, molecular biology, protein/peptide overexpression/synthesis and purification, mechanistic enzymology, coordination chemistry and spectroscopy (UV-Vis, CD, NMR, EPR, etc.), prokaryotic and eukaryotic cell culture, and fluorescence microscopy.