All newly-synthesized polypeptides have to be folded into their three-dimensional structures to be functional. Many proteins have to reach destinations other than cytosol, the site where protein synthesis occurs. In addition, a majority of proteins constantly undergo post-translational modification in response to a wide variety of cellular signals. Therefore, understanding mechanism and regulation of protein folding, protein translocation and protein processing is an integral part of modern molecular and cell biology. In addition, errors in these processes cause diseases ranging from Alzheimer's to Diabetes. Protein folding and processing is one of the major research focuses in our department. Faculty in this area engage in a number of research topics including the unfolded protein response; structure and function of molecular chaperones; heat shock response; protein misfolding in aging and disease; bacterial type III secretion; yeast pheromone processing; protein transport in the secretory pathway; protein targetting and organelle biogenesis.
Structure and function studies in systems biology and the molecular architecture of organelles; development of new technologies and computational tools for proteome analysis with an emphasis on quantitative proteomics and analysis of posttranslational modifications, including phosphoproteomics and analysis of signal transduction pathways.
Determining the role of molecular chaperones and disulfide catalysts in protein folding and experimental evolution of protein folding.
Protein localization and vesicular transport in the eukaryotic secretory/endocytic pathways using budding yeast as a system and employing biochemical reconstitution, cell biology, genetics and fluorescence resonance energy transfer (FRET) microscopy as methods. Protein trafficking in human neurodegenerative and neurodevelopmental disease. Proteolytic processing by enzymes of the SPC/Kex2/furin family in yeast and metazoans with interest in structure-function relationships and discovery of human furin inhibitors as drug models for infectious, degenerative and neoplastic disease.
Studies of protein folding and interactions at the single molecule level; protein misfolding in human disease, specifically how the generation of toxic protein aggregates features in diabetes and Alzheimer's disease.
Use of organic chemistry to build new tools for exploring important biological questions. We are currently focused on generating new technologies for inhibiting protein-protein interactions in neurodegenerative diseases.
The focus of our laboratory is to understand the G protein coupled receptor- mediated signaling of protein hormones in sex hormone producing target tissues on a molecular level. Another ongoing study focuses on post-translational modifications of the LH receptor and their role in ligand-receptor interaction, receptor turn over and intracellular signaling. A third area of interest of the laboratory centers on biochemical studies on the mechanism by which androgens disrupt ovarian follicle development that leads to impaired ovum development, a common cause of reproductive failure in the humans.
Structure-activity relationship and signal transduction pathways of neuropeptides and receptors of the RFamide peptide family and their role in regulating heart rate and muscle contractions.
Reconstitution of signal transduction systems from purified components, structure/function analysis of signal transduction enzymes, protein crystallography. Characterization of protein kinases, phosphatases, and nucleotide transferases involved in signal transduction. Organization of the gene cascade controlling nitrogen assimilation in bacteria. Development of synthetic systems that perform useful functions.
The Saper lab studies the molecular mechanisms of how pathogenic bacteria produce and secrete a large capsule polysaccharide that enhances bacterial virulence. In particular, we focus on a regulatory tyrosine kinase and phosphatase in pathogenic E. coli. Techniques include enzyme kinetics and X-ray crystallography.
Mechanisms that maintain the properly folded state of proteins and promote the degradation of misfolded and denatured proteins are fundamental to the homeostasis of the crowded cellular environment. Malfunction of these processes leads to protein aggregation and the progression of many diseases including Alzheimer’s disease and cancer. Molecular chaperones are at the interface of these processes, serving as a critical triage center for numerous substrate ‘client’ proteins including transcription regulators and cell cycle kinases.
Molecular mechanisms of protein biogenesis including protein folding, membrane trafficking, and stress response; structural biology of protein-protein interaction and molecular recognition using X-ray crystallography.
The main focus of our lab is to develop bioinformatics algorithms to predict 3-dimensional structures of protein molecules from amino acid sequences and deduce the biological functions based on the sequence-to-structure-to-function paradigm. We are also working on protein-ligand docking, protein design, RNA alternative splicing and new drug discovery.
Our lab works on finding inhibitors for the Hsp70 chaperones. Hsp70's have been implicated in cancer cell survival, and in protein folding diseases such as Alzheimer's and Parkinson's. Our lab uses NMR spectroscopy to elucidate the mechanism of the chaperones, and to find and characterize, in collaboration with the Jason Gestwicki lab, potential inhibitors.