Exploring the molecular mechanics of life
Our lab uses various biophysical techniques including cryo-electron microscopy as tools to study the function of macromolecular assemblies. Of particular interest are the atomic details of protein folding as carried out by chaperonins like hsp60/10. Efficient and correct protein folding is critical in preventing misfolded protein aggregation that can lead to loss of function and even disease. This research investigates the protein folding mechanism of human mitochondrial chaperonin though a detailed analysis of its three-dimensional structure using X-ray crystallography and cryo-electron microscopy (cryo-EM). The mtHsp60 D29G and V98I missense mutations have shown direct correlation to hereditary spastic paraplegia type 13 (SPG13) and mitochondrial Hsp60 chaperonopathy (MitCHAP-60). We study various mtHsp60 protein folding intermediates with a focus on the disease-causing point mutations, D29G and V98I, leading to possible treatments.
Charcot-Marie-Tooth disease (CMT) and Distal Hereditary Motor Neuropathy (dHMN) cause dysfunction in nerves of the peripheral nervous system. Our studies aim to facilitate development of strategies for disease intervention through new effective drug therapies by determining the structure of Hsp27 in complex with its client proteins. We are also looking into the role of hsp27 in Alzheimer's and Parkinson's disease and how hsp27 may affect the formation of toxic oligomers and abnormal intracellular aggregates of tau and alpha-synuclin proteins.
Bacteriophages, viruses that specifically infect bacteria, are becoming increasingly relevant in human health with the emergence of antibiotic resistant bacteria and recent bacterial contamination of produce. Pseudomonas aeruginosa is a human pathogen that is responsible for opportunistic multi-drug resistant infections in burn victims, HIV-related bronchial-pulmonary infections and chronic infections in the lungs of cystic fibrosis patients. Our research involves a structural proteomics approach to study Pseudomonas specific bacteriophages that have a potential for use in industrial applications or phage therapy. These studies aim to enhance our understanding of bacteriophage infection mechanisms by determining the structure of various assembly intermediates to high resolution.
This project aims to elucidate the structural and functional roles of DapE, DapD, and DapF for future targeting with inhibitory compounds, using the advanced structural biology technique of cryo-electron microscopy to determine the mechanism of interaction between the enzymes. Pathway enzymes generally will work in concert with each other through complex formation termed a metabolon. A metabolon is a transient multi-enzyme complex that mediates substrate channeling from one enzyme to the next. The metabolon increases efficiency and control of the metabolic flux by having enzymes interacting sequentially, passing the substrates and products directly to the active site of the next enzyme through a molecular tunnel or tether created by the protein-protein complex
CAX-1 is a plant vacuolar proton/calcium ion exchanger whose function is to maintain calcium homeostasis and to mediate responses to external stresses. It is expressed primarily in leaves where it contributes to tolerance of submergence, anoxic environments, and controls recovery production of reactive oxygen species. CAX1 facilitates the transport of calcium ions (Ca2+) from the cytosol into the vacuole, which helps to regulate calcium concentration, stomatal aperture, and plant growth. There is no structure of this plant membrane protein and so we are looking to get the structure either by X-ray crystallography or cryo-Electron Microscopy.