Research

Macromolecules rarely operate in isolation inside cells. At any given time, the average protein is part of a complex of over ten macromolecules, and these supramolecular complexes are in turn embedded in intricate networks inside cells. We are broadly interested in revealing the structure and function of macromolecular complexes in their natural environment at the highest possible resolution in order to reveal their structural dynamics and interactions. We call it bringing structure to cellular biology.

Method Development
Our goal is to build tools for quantitative cell biology, using cryo-electron microscopy and tomography, cell biophysics, computational analysis, and integrative modeling. This potent combination allows us to look at macromolecular complexes in their native environment and derive their structure, context, and interaction partners.
LRRK2 in Parkinsons Disease

We study LRRK2, the major cause of familial Parkinson’s disease.  Using our tools, we have determined the first in situ structure of LRRK2, revealing the interaction between LRRK2 domains and microtubules, and the dimerization interfaces that lead to this putative pathogenic state.  Upon mapping known genetic and sporadic mutations, our structure will help in the design of inhibitors, and to understand the mechanistic details of LRRK2 function.

The Nuclear Periphery
Our current research is focused on studying the nuclear periphery, as nuclear biology remains one of the most exciting challenges in the cell, and it is uncharted territory structurally.

Our thrust in this area includes projects such as: the structural dynamics of the yeast nuclear pore complex, the mechanical communication between the cytoskeleton and the nucleus, and the molecular architecture of the genome and its association to the nuclear envelope.

Bacterial Cell Biology

We collaborate with various laboratories to open windows into various cellular events in bacteria. With Kit Pogliano we study bacterial engulfment, with Susan Golden we study the molecular basis of circadian rhythm, and with Joe Pogliano we study how phage-infected bacteria have sophisticated cellular biology similar to eukaryotes, such as  a cytoskeletal filaments and a nucleus-like compartment.