|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|
|Date Published||2011 Jan 25|
|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|
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.
|Alternate Journal||Proc. Natl. Acad. Sci. U.S.A.|
|PubMed Central ID||PMC3029709|
Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic beta2-microglobulin variant.