Carl Frieden, PhD

Carl Frieden, PhD

Professor, WashU Biochemistry & Molecular Biophysics

Protein folding, structure

Apolipoproteins are essential for lipid and cholesterol transport and metabolism. ApoE4 is one of a family of three apoE proteins. While there are several genetic risk factors for late-onset AD (onset after age 60), the original observation made in 1993 that the ε4 allele is a genetic risk factor still holds. In fact. apoE4 is the major risk factor for Alzheimer’s disease (AD). It is now known that the ε4 allele of apoE increases risk ~3-fold when present in 1 copy and ~12-fold when present in 2 copies relative to the ε3 allele. The three common isoforms of apoE, a protein of 299 amino acids, differ only in two amino acids at positions 112 and 158. We are examining how these single amino acid changes can give rise to 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.

We are studying the molecular properties of the interaction of apoE isoforms with lipids and with Aβ using biophysical techniques. We are also screening a small set of compounds that may preferentially affect the behavior of apoE4 relative to apoE3.

The Tau protein

The protein called tau is responsible for the formation of tangles associated with AD. We have started a project investigating the interaction of apoE proteins with tau.

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.

More about the Frieden lab