Research in our lab focuses on structural biology. We are interested in glycoproteins, particularly those implicated in human disease. Recent structural results on three topics include:

Lysosomal storage diseases: In the lysosome, breakdown of glycoproteins and glycolipids occurs via the action of proteases, lipases, and glycosidases. Our lab is interested in the function and trafficking of lysosomal enzymes, required components in the catabolism of macromolecules. Deficiencies in these enzymes result in the accumulation of their substrates, which eventually leads to the symptoms of lysosomal storage diseases (a family containing over 40 members including Gaucher, Tay-Sachs, and Fabry diseases). These enzymes represent model systems for studying human genetics, because the associated diseases tend to be single gene rather than more complicated polygenic diseases. We have determined the x-ray crystallographic structures of two lysosomal glycosidases, α-N-acetylgalactosaminidase (α-NAGAL) and α-galactosidase (α-GAL), as well as complexes with their catalytic products. The structures revealed the locations of the hundreds of individual point mutations leading to Schindler and Fabry diseases and indicated the atomic basis for enzymatic failure in patients.

Malarial surface proteins: Through the course of its life cycle, the malaria parasite Plasmodium expresses scores of receptors on its surface. These receptors function in cell adhesion, entry into host cells, and immune system evasion. Due to their accessibility on the surface of the parasite and their functional importance, many show promise as vaccine candidates. We have solved the structure of the immunologically important portion of the vaccine candidate MSP-1, a GPI linked protein expressed on the surface of the merozoite form of the parasite. As a requirement for invasion into the red cell of a mammalian host, MSP-1 undergoes two proteolytic processing stages. We have solved the structure of the two domains anchored to the parasite membrane at the end of the invasion process. Host antibodies against these two domains confer protection against malaria infection.

Antibody-receptor interactions: Fc receptors are found on the surface of immune cells, where they couple the exact specificity of antibodies to the specialized effector functions of different immune cells. Fc receptors bind antibodies distal to the antigen binding site on the antibody. In the case of mast cells, the high affinity IgE Fc receptor (FcεRI) binds the IgE antibody, and the appearance of specific antigens (such as allergens) causes crosslinking of the IgE:Fc receptor complexes. This crosslinking initiates a src kinase-mediated signal transduction pathway in the cell, leading minutes later to the degranulation of the mast cell and to the subsequent appearance of allergic symptoms. We have solved the crystal structures of the human IgE Fc receptor, both alone and in complex with the Fc portion of IgE.