Structure of the Protein Homeostasis Machinery
To understand human disease processes, it is necessary to understand the structure and function of the macromolecules and macromolecular interactions that lead to the disease. For example, organisms respond to their environment by activating signaling pathways that lead to specific cellular responses. These responses are propagated by macromolecular interactions, and aberrant signaling leads to cellular dysfunction and disease. Identifying and characterizing macromolecular interactions in cells are critical for a comprehensive understanding of the underlying cause of disease.
Members of the structural biology subgroup are developing cutting-edge approaches towards understanding the molecular basis of disease. Their core strength in basic mechanisms underlying disease processes syngergizes with the applied approaches taken by the pharmaceutical and biotechnology industries.
The Protein Homeostasis research theme has signficant strength in the structural biology of macromolecules and their higher order complexes, with a particular interest in how their dysfunction leads to human disease. A broad range of approaches is used to interrogate macromolecular structure, including X-ray crystallography (Garman and Hardy), NMR spectroscopy (Gierasch and Hardy), and mass spectrometry (Vachet and Kaltashov). Using these and other biophysical approaches, investigators are examining the molecular interactions at the heart of a range of human diseases.
For example, researchers have studied the structural basis of pharmacological chaperoning in lysosomal storage diseases (Garman), the conformational changes in caspases pointing to new avenues for controlling apoptosis (Hardy), and conformational changes in Heat Shock Protein 70 (HSP70) during its role in chaperoning nascent polypeptide chain (Gierasch).
Using mass spectrometry investigators have probed the lifetime of biologics manufactured by the pharmaceutical industry (Kaltashov), dissected the aggregation pathway of proteins that become toxic during kidney dialysis (Vachet), and worked out the interactions between small heat shock proteins and their clients (Vierling).