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

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 ?2-microglobulin (?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 ?2m (?N6?2m). The crystal structure of ?N6?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 ?-sheet. The ?-strands of this sheet are prone to self-associate and stack perpendicular to the direction of the strands to build large intermolecular ?-sheets that run parallel to the axis of growing oligomers, providing an elongation mechanism by self-templated growth.

SUBMITTER: Domanska K 

PROVIDER: S-EPMC3029709 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature