Research

The bacterial cell envelope is one of nature's most sophisticated protective barriers. It shields bacteria from environmental stress and antibiotics while remaining dynamic enough to support growth and survival. We are fascinated by how bacteria build, maintain, and remodel this remarkable structure.

Our research focuses on understanding the molecular mechanisms that regulate lipopolysaccharide (LPS) synthesis, transport, and assembly, and how these processes are coordinated with other components of the cell envelope. These fundamental questions are not only central to bacterial physiology but also provide exciting opportunities for developing new antibiotics against multidrug-resistant Gram-negative pathogens.

Rather than relying on any single technique, we use whatever tools are needed to answer the biological question. Our work integrates structural biology, biochemistry, microbiology, genetics, biophysics, and computational modeling. We are enthusiastic users of cryo-EM—but we don't collect structures just because we can. Every experiment, whether it produces a structure, a mutant, or a simulation, is designed to help explain how the system works.

Lipopolysaccharide (LPS) is the defining component of the outer membrane of Gram-negative bacteria, forming a protective barrier that shields these pathogens from antibiotics and host immune defenses. Because both insufficient and excessive LPS are detrimental, its biosynthesis must be precisely regulated. Our laboratory seeks to understand the molecular mechanisms that maintain this delicate balance.

Our research has revealed the molecular framework of the FtsH–LapB–YejM regulatory pathway, providing a mechanistic view of how Gram-negative bacteria control LPS synthesis through regulated degradation of LpxC, the enzyme that catalyzes the committed step of LPS biosynthesis. By integrating structural biology, biochemistry, microbiology, and genetics, we demonstrated how the membrane proteins YejM, LapB, and FtsH coordinate LpxC degradation in response to changes in LPS homeostasis.

Our studies also uncovered an unexpected second role for LapB. Beyond serving as the adaptor that delivers LpxC to the FtsH protease for degradation, LapB directly inhibits LpxC enzymatic activity. This dual regulatory mechanism enables bacteria to control both the abundance and activity of LpxC, providing an elegant strategy to fine-tune LPS production in response to cellular demands.

Building on these discoveries, we continue to investigate how bacterial cells coordinate envelope biogenesis and maintain LPS homeostasis. We are equally committed to translating these mechanistic insights into new therapeutic strategies and developing next-generation antibiotics to combat multidrug-resistant Gram-negative pathogens.

In addition to our independent research program, we actively collaborate with investigators at Yale and other institutions to understand the structures and mechanisms of medically important membrane proteins. Our laboratory brings expertise in cryo-electron microscopy (cryo-EM), structural biology, biochemistry, and mechanistic analysis to address challenging biological questions.

Our collaborative projects span a diverse range of membrane proteins involved in receptor signaling, intracellular transport, nuclear envelope biology, and neurological diseases. By working closely with outstanding collaborators, including Yossi Schlessinger, Dan Wu, and others, we seek to uncover how these molecular machines function and how their dysregulation contributes to human disease.

We view each collaboration as an opportunity not simply to determine a structure, but to reveal the molecular mechanisms underlying protein function. By integrating structural and biochemical approaches, we aim to generate insights that advance both fundamental biology and future therapeutic development.