Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 4, Pages 1314-1319Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008560108
Keywords
crystallization chaperones; amyloid fibrils; prefibrillar intermediates; dialysis-related amyloidosis
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Funding
- Interuniversity Attraction Poles [P6/19]
- Ministero dell'Istruzione
- dell'Universita e della Ricerca (Fondo per gli Investimenti della Ricerca di Base and Programmi di Ricerca di Interesse Nazionale)
- European Union [LSHM-CT-2005-037525]
- Fondazione Cariplo and Regione Lombardia
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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 beta 2-microglobulin (beta 2m) amyloidogenesis by X-ray crystallography. For this purpose, we selected five single domain antibodies that block the fibrillogenesis of a proteolytic amyloidogenic fragment of beta 2m (Delta N6 beta 2m). The crystal structure of Delta N6 beta 2m 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 beta-sheet. The beta-strands of this sheet are prone to self-associate and stack perpendicular to the direction of the strands to build large intermolecular beta-sheets that run parallel to the axis of growing oligomers, providing an elongation mechanism by self-templated growth.
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