title: Secondary structure in the core of amyloid fibrils formed from human β₂m and its truncated variant ΔN6.
abstract: Amyloid fibrils formed from initially soluble proteins with diverse sequences are associated with an array of human diseases. In the human disorder, dialysis-related amyloidosis (DRA), fibrils contain two major constituents, full-length human β2-microglobulin (hβ2m) and a truncation variant, ΔN6 which lacks the N-terminal six amino acids. These fibrils are assembled from initially natively folded proteins with an all antiparallel β-stranded structure. Here, backbone conformations of wild-type hβ2m and ΔN6 in their amyloid forms have been determined using a combination of dilute isotopic labeling strategies and multidimensional magic angle spinning (MAS) NMR techniques at high magnetic fields, providing valuable structural information at the atomic-level about the fibril architecture. The secondary structures of both fibril types, determined by the assignment of ~80% of the backbone resonances of these 100- and 94-residue proteins, respectively, reveal substantial backbone rearrangement compared with the location of β-strands in their native immunoglobulin folds. The identification of seven β-strands in hβ2m fibrils indicates that approximately 70 residues are in a β-strand conformation in the fibril core. By contrast, nine β-strands comprise the fibrils formed from ΔN6, indicating a more extensive core. The precise location and length of β-strands in the two fibril forms also differ. The results indicate fibrils of ΔN6 and hβ2m have an extensive core architecture involving the majority of residues in the polypeptide sequence. The common elements of the backbone structure of the two proteins likely facilitates their ability to copolymerize during amyloid fibril assembly.
authors.affiliation: Department of Chemistry and Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology Cambridge, Massachusetts 02139, United States.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Su
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Sarell
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Eddy
authors.forename: Galia T
authors.initials: GT
authors.lastname: Debelouchina
authors.forename: Loren B
authors.initials: LB
authors.lastname: Andreas
authors.forename: Clare L
authors.initials: CL
authors.lastname: Pashley
authors.forename: Sheena E
authors.initials: SE
authors.lastname: Radford
authors.forename: Robert G
authors.initials: RG
authors.lastname: Griffin
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D017384:Sequence Deletion; D001613:beta 2-Microglobulin / Q000737:chemistry* / Q000235:genetics*
chemical_list: D000682:Amyloid; D001613:beta 2-Microglobulin