title: Polyglutamine fibrils are formed using a simple designed beta-hairpin model.
abstract: Polyglutamine repeats are found in proteins associated with many neurodegenerative diseases. These repeats are responsible for intracellular protein aggregation that resemble amyloid plaques and contain the hallmarks of cross-beta fibrillar structures. Recent work has suggested that the glutamines are involved in aggregation through two possible mechanisms: one involving only side-chain hydrogen bonding and a second involving interdigitation of the glutamines with tight van der Waal's packing (steric zipper model). We are interested in determining which interactions are particularly involved in early assembly processes and have developed a beta-hairpin model system to address this problem. Our model system is designed to stabilize a putative high-energy nucleating structure to provide a window to view early assembly processes. We have applied spectroscopy tools (circular dichroism, infrared, and dynamic light scattering) to probe the self-assembly of beta-sheet fibrils. These experiments established the conditions to study fibrillar morphology using atomic force microscopy. We show that fibrils are short with minimal lateral growth, suggesting that this may be a good model system for studying early assembly steps.
authors.affiliation: Department of Biology, Haverford College, Haverford, Pennsylvania 19041, USA.
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Smith
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Miles
authors.forename: Molly
authors.initials: M
authors.lastname: Sheehan
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Alfieri
authors.forename: Bashkim
authors.initials: B
authors.lastname: Kokona
authors.forename: Robert
authors.initials: R
authors.lastname: Fairman
mesh_terms: D006863:Hydrogen-Ion Concentration; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D010455:Peptides; C097188:polyglutamine