Title | Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic beta2-microglobulin variant. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Domanska, K., S. Vanderhaegen, V. Srinivasan, E. Pardon, F. Dupeux, J. A. Marquez, S. Giorgetti, M. Stoppini, L. Wyns, V. Bellotti, and J. Steyaert |
Journal | Proc Natl Acad Sci U S A |
Volume | 108 |
Issue | 4 |
Pagination | 1314-9 |
Date Published | 2011 Jan 25 |
ISSN | 1091-6490 |
Keywords | Amino 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. |
DOI | 10.1073/pnas.1008560108 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 21220305 |
PubMed Central ID | PMC3029709 |
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