Complex modular transmembrane receptors mediate a wide variety of cellular processes, including specific uptake of target ligands, transduction of extracellular signals, and viral entry into cells. Our research program is devoted to elucidating the detailed molecular basis for specificity in ligand recognition by modular cell surface receptors of the LDL and Notch receptor families.

The LDL receptor (LDLR) is the primary mechanism for uptake of cholesterol-carrying lipoprotein particles into cells. Binding of lipoproteins is mediated by the amino-terminal domain of the receptor, which consists of seven tandemly repeated modules. Each module is 40 amino-acid residues long and contains three disulfide bonds. Others have shown that several of these modules are required for binding of LDL, but that the fifth module is most important for recognition of lipoproteins containing apolipoprotein E.

Is the ligand-binding domain of the LDLR flexible, or is it rigid and filamentous? Do adjacent ligand-binding modules significantly interact with each other, or are they truly independent structural elements tethered by a short, flexible spacer? To address these questions, we are evaluating the structure and dynamics of the module five-six pair of the LDLR by NMR. Subsequently, we plan to identify specific contacts between the ligand and the receptor, evaluate the contributions of individual amino acids to ligand-binding, and understand how disease-causing point mutations within the receptor give rise to FH.

The human Notch1 (TAN-1) gene, originally discovered at the breakpoint of a recurrent chromosomal translocation found in human acute T-cell lymphoblastic leukemias, is a member of a conserved family of receptors that control differentiation in multicellular animals. Although these receptors are large and complex, all Notch family members contain a conserved extracellular domain consisting of three LIN12 modules that are required for proper control of signaling. We are currently determining the structure of a prototype LIN12 module of human Notch1 by NMR, and in collaboration with the laboratory of Dr. Jon Aster, studying the detailed role of these LIN12 modules in regulating Notchi receptor function.