Associate Professor Matthew R. Chapman
"Protein Misfolding Done Right: The Biogenesis of Bacterial Amyloids"
Abstract:
Amyloid formation has a nefarious history. Linked to protein misfolding and cytotoxicity, amyloids are the hallmark of several neurodegenerative diseases including Alzheimer’s and Parkinson’s. However, amyloid formation is not always bad. In fact, organisms spanning nearly every facet of cellular life produce ‘functional’ amyloids that contribute positively to cellular biology. Bacterial functional amyloids called curli are the major proteinaceous component of the extracellular matrix, and they help protect the cells during biofilm growth. Curli also provide a sophisticated suite of genetic and biochemical tools for understanding how cells coordinate and control amyloid formation. The major curli subunit is CsgA, which is highly amyloidogenic, although the cell has powerful mechanisms for discouraging intracellular CsgA amyloid formation. We have characterized several E. coli chaperones for their ability to deter CsgA amyloid formation, including two proteins that work specifically during curli biogenesis. These two proteins, called CsgC and CsgE, are periplasmic proteins with unique and potent anti-amyloid properties. The anti-amyloid properties of CsgC will be discussed. Interestingly, we found that CsgC also prevented amyloid formation by α-synuclein, the underlying cause of Parkinson’s disease. A common Q-X-G-X1/2-N-X5-Q motif was identified in CsgC client proteins, including α-synuclein. We are currently looking the anti-amyloid properties of a human protein called transthyretin (TTR) that shows remarkable structural homology to CsgC. When CsgA is co-incubated with either human TTR fibrillogenesis is inhibited. The biologic implementation of the TTR-CsgA interaction was assessed by observing the effect of TTR on amyloid-dependent biofilm formation by two different bacterial species using a pellicle forming assay. Biofilm formation was substantially inhibited by both the TTR tetramer and engineered monomer. Therefore, both TTR and CsgC behave as a chaperone-like proteins that discourage amyloid formation. It is possible that this phenomenon might be utilized to enhance antibiotic efficacy in infections associated with significant biofilm formation.
Amyloid formation has a nefarious history. Linked to protein misfolding and cytotoxicity, amyloids are the hallmark of several neurodegenerative diseases including Alzheimer’s and Parkinson’s. However, amyloid formation is not always bad. In fact, organisms spanning nearly every facet of cellular life produce ‘functional’ amyloids that contribute positively to cellular biology. Bacterial functional amyloids called curli are the major proteinaceous component of the extracellular matrix, and they help protect the cells during biofilm growth. Curli also provide a sophisticated suite of genetic and biochemical tools for understanding how cells coordinate and control amyloid formation. The major curli subunit is CsgA, which is highly amyloidogenic, although the cell has powerful mechanisms for discouraging intracellular CsgA amyloid formation. We have characterized several E. coli chaperones for their ability to deter CsgA amyloid formation, including two proteins that work specifically during curli biogenesis. These two proteins, called CsgC and CsgE, are periplasmic proteins with unique and potent anti-amyloid properties. The anti-amyloid properties of CsgC will be discussed. Interestingly, we found that CsgC also prevented amyloid formation by α-synuclein, the underlying cause of Parkinson’s disease. A common Q-X-G-X1/2-N-X5-Q motif was identified in CsgC client proteins, including α-synuclein. We are currently looking the anti-amyloid properties of a human protein called transthyretin (TTR) that shows remarkable structural homology to CsgC. When CsgA is co-incubated with either human TTR fibrillogenesis is inhibited. The biologic implementation of the TTR-CsgA interaction was assessed by observing the effect of TTR on amyloid-dependent biofilm formation by two different bacterial species using a pellicle forming assay. Biofilm formation was substantially inhibited by both the TTR tetramer and engineered monomer. Therefore, both TTR and CsgC behave as a chaperone-like proteins that discourage amyloid formation. It is possible that this phenomenon might be utilized to enhance antibiotic efficacy in infections associated with significant biofilm formation.
| Building: | Chemistry Dow Lab |
|---|---|
| Event Type: | Workshop / Seminar |
| Tags: | Biophysics, Chemistry |
| Source: | Happening @ Michigan from LSA Biophysics |
