Research in my laboratory centers on biological molecules and how they function in the cell. We seek new insights into the ways in which living systems function and evolve at the molecular level. We use multi-dimensional approaches with a particular emphasis on structural biology to study the structure and function relationship of proteins related to in vivo protein folding, trafficking and stress response.
Protein folding: Protein folding problems have been directly linked to many disease states including cystic fibrosis, diabetes, various clotting disorders, and neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. Molecular chaperones function to assist other proteins to overcome obstacles they face in attaining their native structures in vivo. Our group was the first one to determine the long sought-after structure of chaperone SecB (1), which plays a pivotal role in protein secretion across the bacterial plasma membrane. We followed that work by determining the structure of SecB in complex with its membrane receptor SecA (2). More recently, our group published the structure of another very important molecular chaperone, trigger factor, a protein that serves as the “welcoming committee” for nascent polypeptides exiting the ribosome (3).
Protein Trafficking: Eukaryotic cells are elaborately subdivided into functionally distinct, membrane-enclosed compartments. Communication among these compartments, with protein molecules being passed from a donor compartment to a target compartment, is achieved by means of membrane-enclosed transport vesicles. We are interested in understanding the molecular mechanism that regulates these processes. In particular, we focus our attention on the structures of protein complexes involved in mediating in vivo vesicle trafficking. Two of recently studied protein structures in the lab are Exo70, a subunit of an octameric protein complex called exocyst that is responsible for vesicle tethering to the plasma membrane during exocytosis, and Vps4, an AAA+ protein that functions in the endocytic multi-vesicular bodies pathway that plays an important role in cell surface receptor down-regulation.
Unfolded Protein Response: We have also made major breakthroughs in understanding the structure and function relationship of molecules involved in the unfolded protein response (UPR). The UPR is a stress-induced cellular adaptive response that coordinates the protein-folding demand with the protein-folding capacity of the endoplasmic reticulum (ER). A class of novel ER trans-membrane receptors including IRE1, PERK, and ATF6 detect the accumulation of unfolded proteins in the ER lumen and signal downstream responses. We have determined the crystal structure of the lumenal domain of human IRE1 and shown that the structure comprises a unique fold of a triangular assembly of three beta sheet clusters (4, 5). Mutagenesis studies demonstrate that dimerization of this domain constitutes a novel conserved mechanism required by IRE1 and PERK for autophosphorylation and to signal the unfolded protein response.