Lea Lab

About the Lea lab

Understanding the structural nuances surrounding how and why multiprotein complexes assemble enhances our ability to understand basic biological questions and identify molecular drivers of disease. Multiprotein complexes regulate a wide range of essential cellular functions in both prokaryotic and eukaryotic cells, and aberrant assemblages of these complexes can disrupt key cellular processes. The Lea laboratory uses structural biological approaches to understand bacterial pathogenesis as well as address biological questions of direct medical relevance, ranging from inter-cellular communication to immune regulation and cell division.

The team

The Lea lab is a diverse group of multidisciplinary scientists interested in utilizing structural biology to understand a wide range of biological systems.

Meet the team

Our research summary

Bacterial systems and mammalian membrane proteins

Our laboratory applies biophysical approaches to study the bacterial processes underpinning pathogenesis. In a seminal study, we utilized cryo-electron microscopy (cryo-EM) to generate atomic models of the flagellar basal body and mechanistically defined the proton-powered motors responsible for rotational switching of the bacterial flagellum. These results have profoundly altered the field’s understanding of bacterial movement machinery. Additionally, we are interested in studies pertaining to bacterial secretion and motility systems. Our structural approach is aiding in elucidating the molecular mechanisms involved in bacterial secretion, motility, and phage evasion.

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We also apply innovative biophysical approaches to obtain structures of proteins involved in human biology. Ongoing projects in the lab probe function, disease states, and drug targeting across proteins involved in protein/lipid trafficking, protein folding pathways, and the transport of peptides and small molecules. Notably, our work provided the structure of a folate-transporter, PCFT, interacting with a clinically relevant cancer therapeutic drug. This structural information has laid the foundation for a next-generation therapeutic which stands to have greater specificity and less toxicity.

Innate immune system

Our team is also interested in understanding the mechanisms governing the Complement system, an innate immune component that uses enzymatic cascades to elicit appropriate host defenses against initial infection. Our team identifies pathogenic proteins which hijack the Complement system and promote pathogenicity. Our findings have highlighted the fact that serum protein cascades are integrated in such a way that the innate response, contact activation, and coagulation systems are all interconnected, and we are now focused on probing this complex relationship. Already, we have developed methodology allowing us to structurally elucidate a complex containing the anti-coagulant Protein S and the complement regulatory protein, C4bp, thereby providing critical evidence of this crosstalk and setting the stage for future studies.

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The cutting edge of cryo-EM

Because of the nature of the biological questions we ask and the difficulty of the systems in which we work, our team is experienced in novel method development for cryo-EM. Our strong collaborations aid us in developing and optimizing workflows for challenging cryo-EM targets.