Molecular Biophysics Program
Molecular Cell Biology Program
Dr. Carl Frieden, Dr. Qin Shu, Dr.
Sudha Cowsik, Dr. Melissa Brereton, Berevan Baban,
Dr. Linda Kurz and Dr. George Drysdale.
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Problem Set Answers
|Biochem 5325 - Lectures notes|
ApoE proteins and Alzheimer's DiseaseWhile apolipoproteins are essential for lipid and cholesterol metabolism one such protein in the brain, called ApoE4 is the major risk factor for late-onset (onset after age 60), Alzheimer's disease (AD). It is now known that individuals with two copies of apoE4 will almost certainly develop AD. ApoE3, the common form of apoE, differs from apoE4 by a just a single amino acid (out of 299) but is benign with respect to developing AD. Thus the two proteins are functionally different. We are examining, using biophysical and other techniques, how this single amino acid change can give rise to these functional differences.
Amyloid beta, Aβ, is a small peptide associated with plaques in those who have Alzheimer's Disease. Genetic, biochemical, and animal model studies strongly suggest that apoE4 is likely to influence Alzheimer's Disease pathogenesis via effects on the metabolism of the 38-43 amino acid amyloid-β (Aβ) peptide.
Curli proteins. Bacterial communities, called biofilms, are important in various types of infections, including urinary tract infections (UTIs), chronic skin wounds, otitis media and lung infections in cystic fibrosis patients. For E. coli and other Enterobacteriaceae biofilms, adhesive amyloid fibers called curli can be a major proteinaceous constituent of the extracellular matrix. Curli promote biotic and abiotic surface colonization, stabilize cell-cell contacts allowing cell aggregation and thickening of the biofilm layer, and confer resistance to the biofilm against environmental stresses and biocides. The structural subunits of curli amyloid fibers are CsgA (major component) and CsgB (minor component), CsgE and CsgF which may serve a chaperone function and CsgG, a lipoprotein that localizes to the outer membrane as an oligomeric pore structure and is required for the export of curli subunits to the cell surface. Both CsgA and CsgB are intrinsically disordered proteins (IDPs). In vitro, CsgA and CsgB can self-associate to form high molecular weight aggregates/fibrils. We are studying the properties of the curli subunits and their mechanism of aggregation.
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Protein folding, protein dynamics, protein structure/function
relationships, protein-protein interactions and polymerization/aggregation
mechanisms are projects that we have studied in this laboratory.
Protein FoldingThe long term goal of the protein folding studies was to understand the nature of the unfolded and intermediate structures on the unfolding and refolding pathways, including the role of proteins that assist folding (called chaperonins). The work uses site-directed mutagenesis and techniques such as 19F and proton NMR, circular dichroism, fluorescence measurements and x-ray crystallography. Current studies include work with the apoE family of proteins, with the role of proline in protein folding and with intrinsically disordered proteins such as amyloid beta and the bacterial protein CsgA. Many of the studies involved incorporating fluorine labeled amino acids into the protein and then examining the NMR spectrum. We use stopped flow methods in conjunction with a fluorine cryoprobe for these measurements. From data collected in current and past projects we have a large database of fluorine chemical shifts in proteins. These shifts are sensitive to low concentrations of denaturant, to temperature and to pH. A website for fluorine chemical shifts has been established at http://biochem.wustl.edu/~bmbnmr/Fluorine.html.
You can download the newest versions of Kinsim and Fitsim for the PC
from this site. Click Here to
view the release notes and download the compressed file. You will also
find a link to a short help page.
NOW YOU CAN RUN KINSIM AND FITSIM ON YOUR MAC!
Requires downloading a DOS emulator like DOSBOX (which is free).
Click here for instructions. Instructions using DOSBOX were written by Scott Crick.
Dr. Carl Frieden
Department of Biochemistry and Molecular Biophysics, Box 8231
Washington University School of Medicine
660 South Euclid
St. Louis, MO 63110 (USA)
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