Research

Structural Immunology and Structure-based Vaccine Design: We are interested in understanding the structural basis of immune recognition of diverse viral and bacterial antigens following natural infection and vaccination. When a virus or bacteria invades its host a huge diversity of antibodies are created which recognize biomolecules produced by the pathogen and either mark it for destruction or prevent it from infecting host cells. Critical to this recognition are the specific interactions between the antibodies and their biomolecular targets. Cryo-EM has rapidly become the technique of choice for studying the atomic details of these antibody-antigen interactions and has dramatically accelerated the pace of research in this area. A highly relevant example is the development of the SARS-CoV-2 vaccine, where cryo-EM structures were directly used to design the pre-fusion stabilized Spike protein and to rapidly assess the diversity of antibody responses from both vaccination and natural infection. Currently, our lab is focused on studying glycosylation of influenza Hemagglutinin and its impact on protein biophysics and viral fitness. In addition, we have an ongoing collaboration with Dr. James Fleckenstein from Washington University in St. Louis focused on the design and characterization of subunit vaccines against Enterotoxigenic Escherichia coli (ETEC) and other enteric pathogens.

Glycoproteins: Many of the viral and bacterial antigens we study are extensively glycosylated, meaning they are modified post-translationally with covalently attached sugar molecules. It is becoming increasingly apparent that these glycans play critical roles in a wide variety of phenomena and can dramatically affect protein structure and function. Despite this, their size, flexibility, and compositional heterogeneity has significantly complicated the structural analysis of glycoproteins by traditional methods. Again, cryo-EM, especially in combination with computational biology tools, has emerged as the premier experimental tool for studying glycoprotein structure because of its remarkable capabilities for overcoming and deciphering the various types of molecular heterogeneity inherent to these biomolecules. As a synergistic pursuit to our goals of understanding immune recognition, we explore protein glycosylation and how it modulates the structure and function of these important viral and bacterial proteins with the aim of designing better immunogens and discovering foundational principles that will apply to glycoproteins more broadly.

Apolipoprotein B100-containing Lipoproteins: Lipoproteins (LPs) are large and heterogeneous macromolecular nanoparticles that play a central role in lipid and cholesterol metabolism by packaging and transporting hydrophobic biomolecules between the liver and peripheral tissue where they are needed for a wide variety of biological processes. Apolipoprotein B100 (apoB), one of the largest and most complex proteins in the human genome, is the primary structural and functional component of all non-high density lipoproteins (LPs) including very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low-density lipoprotein (LDL), and lipoprotien(a) (Lp(a)). ApoB serves three main functions: (1) coordinating the synthesis of LP particles; (2) acting as the primary structural component of LPs to maintain particle integrity; and (3) providing the binding domain for receptors, enabling cellular uptake. Dysregulation of apoB-containing LP metabolism and mutations in apoB contribute to atherosclerosis, metabolic diseases such as diabetes, and a range of inherited lipid disorders. Despite its pivotal role in fundamental lipid biochemistry and human disease, significant gaps remain in our understanding of apoB structure and function. Our lab primarily utilizes cryo-EM in conjunction with other biophysical, molecular, and cellular techniques to interrogate the structure-function relationship of apoB. Our research aims to advance our understanding LP metabolism, provide valuable tools and knowledge to the broader research community, and yield critical insights into the molecular mechanisms underlying various diseases.