Globular tetramers of beta(2)-microglobulin assemble into elaborate amyloid fibrils.
Amyloid fibrils are ordered polymers in which constituent polypeptides adopt a non-native fold. Despite their importance in degenerative human diseases, the overall structure of amyloid fibrils remains unknown. High-resolution studies of model peptide assemblies have identified residues forming cross-beta-strands and have revealed some details of local beta-strand packing. However, little is known about the assembly contacts that define the fibril architecture. Here we present a set of three-dimensional structures of amyloid fibrils formed from full-length beta(2)-microglobulin, a 99-residue protein involved in clinical amyloidosis. Our cryo-electron microscopy maps reveal a hierarchical fibril structure built from tetrameric units of globular density, with at least three different subunit interfaces in this homopolymeric assembly. These findings suggest a more complex superstructure for amyloid than hitherto suspected and prompt a re-evaluation of the defining features of the amyloid fold.
White
Helen E
HE
Department of Crystallography and Institute of Structural and Molecular Biology, Birkbeck College, London, UK.
Hodgkinson
Julie L
JL
Jahn
Thomas R
TR
Cohen-Krausz
Sara
S
Gosal
Walraj S
WS
Müller
Shirley
S
Orlova
Elena V
EV
Radford
Sheena E
SE
Saibil
Helen R
HR
D000682:Amyloid / Q000737:chemistry*; D008958:Models, Molecular; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000737:chemistry; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure
D000682:Amyloid; D021122:Protein Subunits; D001613:beta 2-Microglobulin