Atomic structure of a nanobody-trapped domain-swapped dimer of an amyloidogenic β2-microglobulin variant

被引:96
作者
Domanska, Katarzyna [1 ,2 ]
Vanderhaegen, Saskia [1 ,2 ]
Srinivasan, Vasundara [1 ,2 ]
Pardon, Els [1 ,2 ]
Dupeux, Florine [3 ,4 ]
Marquez, Jose A. [3 ,4 ]
Giorgetti, Sofia [5 ]
Stoppini, Monica [5 ]
Wyns, Lode [1 ,2 ]
Bellotti, Vittorio [5 ]
Steyaert, Jan [1 ,2 ]
机构
[1] Vlaams Inst Biotechnol, Dept Mol & Cellular Interact, B-1050 Brussels, Belgium
[2] Vrije Univ Brussel, B-1050 Brussels, Belgium
[3] European Mol Biol Lab, Grenoble Outstn, F-38042 Grenoble 9, France
[4] Unit Virus Host Cell Interact, F-38042 Grenoble 9, France
[5] Univ Pavia, Dept Biochem, I-27100 Pavia, Italy
关键词
crystallization chaperones; amyloid fibrils; prefibrillar intermediates; dialysis-related amyloidosis; PROTEIN AGGREGATION; ANTIBODY FRAGMENTS; CRYSTAL-STRUCTURE; NEUTRAL PH; DISEASES; BETA(2)-MICROGLOBULIN; MECHANISM; INSIGHTS; SCRAPIE; FIBRILS;
D O I
10.1073/pnas.1008560108
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:1314 / 1319
页数:6
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