2x89

Publication Abstract from PubMed

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 beta2-microglobulin (beta2m) amyloidogenesis by X-ray crystallography. For this purpose, we selected five single domain antibodies that block the fibrillogenesis of a proteolytic amyloidogenic fragment of beta2m (DeltaN6beta2m). The crystal structure of DeltaN6beta2m 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.

Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic {beta}2-microglobulin variant.,Domanska K, Vanderhaegen S, Srinivasan V, Pardon E, Dupeux F, Marquez JA, Giorgetti S, Stoppini M, Wyns L, Bellotti V, Steyaert J Proc Natl Acad Sci U S A. 2011 Jan 10. PMID:21220305^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.