Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic beta2-microglobulin variant.

TitleAtomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic beta2-microglobulin variant.
Publication TypeJournal Article
Year of Publication2011
AuthorsDomanska, K., S. Vanderhaegen, V. Srinivasan, E. Pardon, F. Dupeux, J. A. Marquez, S. Giorgetti, M. Stoppini, L. Wyns, V. Bellotti, and J. Steyaert
JournalProc Natl Acad Sci U S A
Volume108
Issue4
Pagination1314-9
Date Published2011 Jan 25
ISSN1091-6490
KeywordsAmino Acid Sequence, Amyloid, Animals, Antibodies, Antibody Affinity, beta 2-Microglobulin, Camelids, New World, Camels, Crystallography, X-Ray, Electrophoresis, Polyacrylamide Gel, Humans, Microscopy, Electron, Transmission, Models, Molecular, Mutation, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Secondary, Protein Structure, Tertiary, Surface Plasmon Resonance
Abstract

Atomic-level structural investigation of the key conformational intermediates of amyloidogenesis remains a challenge. Here we demonstrate the utility of nanobodies to trap and characterize intermediates of β2-microglobulin (β2m) amyloidogenesis by X-ray crystallography. For this purpose, we selected five single domain antibodies that block the fibrillogenesis of a proteolytic amyloidogenic fragment of β2m (ΔN6β2m). The crystal structure of ΔN6β2m in complex with one of these nanobodies (Nb24) identifies domain swapping as a plausible mechanism of self-association of this amyloidogenic protein. In the swapped dimer, two extended hinge loops--corresponding to the heptapetide NHVTLSQ that forms amyloid in isolation--are unmasked and fold into a new two-stranded antiparallel β-sheet. The β-strands of this sheet are prone to self-associate and stack perpendicular to the direction of the strands to build large intermolecular β-sheets that run parallel to the axis of growing oligomers, providing an elongation mechanism by self-templated growth.

DOI10.1073/pnas.1008560108
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID21220305
PubMed Central IDPMC3029709
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