BIOT 482 |
| In Huntington's and related diseases, proteins with expanded polyglutamine domains are expressed; these proteins aggregate into inclusions that are believed to cause neuronal degeneration. Synthetic polyglutamine peptides are useful models of polyglutamine-containing proteins. A widely accepted hypothesis is that polyglutamine aggregation follows a nucleation-elongation mechanism characterized by a lag time and a monomeric nucleus. We re-examined this hypothesis by measuring the aggregation kinetics of K2Q23K2, using light scattering and size exclusion chromatography. During the putative lag time there is substantial organization of the peptide into soluble linear aggregates. We propose that polyglutamine assembles first via hydrophobic interactions, which then convert into insoluble ß-sheet fibrils via slow conformational changes. Once fibrils form, monomer loss is accelerated, possibly through templated assembly. We established a model system using apomyoglobin as the host protein, and generated a library of mutants containing 16 - 102 glutamines. Detailed characterization of folding, stability, and aggregation of this library is underway. |
|
Biophysical and Biomolecular Symposium: Protein Aggregation
2:00 PM-5:25 PM, Thursday, August 23, 2007 BCEC -- 107C, Oral
Division of Biochemical Technology |