title: Segmental polymorphism in a functional amyloid.
abstract: Although amyloid fibrils are generally considered to be causative or contributing agents in amyloid diseases, several amyloid fibrils are also believed to have biological functions. Among these are fibrils formed by Pmel17 within melanosomes, which act as a template for melanin deposition. We use solid-state NMR to show that the molecular structures of fibrils formed by the 130-residue pseudo-repeat domain Pmel17:RPT are polymorphic even within the biologically relevant pH range. Thus, biological function in amyloid fibrils does not necessarily imply a unique molecular structure. Solid-state NMR spectra of three Pmel17:RPT polymorphs show that in all cases, only a subset (~30%) of the full amino acid sequence contributes to the immobilized fibril core. Although the repetitive nature of the sequence and incomplete spectral resolution prevent the determination of unique chemical shift assignments from two- and three-dimensional solid-state NMR spectra, we use a Monte Carlo assignment algorithm to identify protein segments that are present in or absent from the fibril core. The results show that the identity of the core-forming segments varies from one polymorph to another, a phenomenon known as segmental polymorphism.
authors: Laboratory of Chemical Physics, National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors: Kan-Nian
authors: KN
authors: Hu
authors: Ryan P
authors: RP
authors: McGlinchey
authors: Reed B
authors: RB
authors: Wickner
authors: Robert
authors: R
authors: Tycko
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D003198:Computer Simulation; D018698:Glutamic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009010:Monte Carlo Method; D009500:Neutralization Tests; D058951:gp100 Melanoma Antigen / Q000737:chemistry
chemical_list: D000682:Amyloid; D058951:gp100 Melanoma Antigen; D018698:Glutamic Acid