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Research


Large protein assemblies in nature are universal and essential. They represent a unique gold mine to identify functional modules that display seemingly simple molecular architectures analogous to each LEGO piece; when assembled, they form remarkably complex structures. Our research program aims to discover and understand the biochemical principle behind those nature’s LEGO, especially microbial appendages involved in pathologies, microbial ecology, and bioenergetics. Ultimately, we would like to apply these biochemical rules to design peptide/protein modules that can assemble into functional nanotubes for biomedical applications.

How do microbes make long-range electron transfer happen?

In anoxic environments, from aquatic sediments to the human gut, respiring bacteria naturally transfer electrons on the micron-scale beyond their outer membranes to distant and insoluble terminal electron acceptors. We generated the first atomic structure of Geobacter conductive nanowires (Cell, 2019), and the atomic structure now reveals the unexpected identity of the conductive nanowires to be polymerized hexa-heme c-type cytochromes. Hemes within OmcS fibers are arranged in a continuous axial chain inside the fiber core, with inter-heme distances from ~3.5-6.0 Å. This is an exciting and new area of research, and our lab uses cryo-EM to understand and design heme-based microbial conductive nanowires.

Bacterial pili, dynamics, and function

A significant proportion of prokaryotic cells invest substantial energy in producing extracellular appendages, known as flagella and pili, which extend microns from the cell surface. Historically, all hair-like, non-flagellar appendages on bacterial surfaces were broadly classified as "pili," but it is now clear that there are distinct classes of pili with very different functions. We and others are continuously discovering new classes of pili. These protein polymers, often comprising over ten thousand protein subunits per filament, impose considerable metabolic demands on bacteria, including protein synthesis, transport, assembly, and the subsequent operation of the appendage.  This considerable energy expenditure underscores the importance of these appendages in bacterial survival and adaptation to diverse environments. The long-term goal of my research program is to integrate structural, biophysical, genetic, and protein engineering approaches to understand the structure, production regulation, and function of microbial appendages, particularly in the context of pathogenic bacteria. 

Nanotube design in new frontiers in anti-tumor nanomedicine

The rationale and motivation for this project are: we have observed many fascinating functions from viruses and microbial pili. However, they cannot self-assemble and a large assembling machine is typically needed to put them together, which greatly limits their engineering potential and biomedical applications. While protein self-assembly is a ubiquitous phenomenon in nature, we aim to combine prior knowledge and design self-assembled nanotubes with different structural modules for new biomedical purposes, especially for cancer therapy.

What we do

Use cryo-EM to understand and design large assemblies

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