学術雑誌論文

学術雑誌論文

text

Journal of Biological Chemistry. 2013, 288(43), p. 30917-30930

Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN

American Society for Biochemistry and Molecular Biology

英語

text

2013-10

https://doi.org/10.1074/jbc.M113.498857

This research was originally published in the Journal of Biological Chemistry. P. Patrizia Mangione, Gennaro Esposito, Annalisa Relini, Sara Raimondi, Riccardo Porcari, Sofia Giorgetti, Alessandra Corazza, Federico Fogolari, Amanda Penco, Yuji Goto, Young-Ho Lee, Hisashi Yagi, Ciro Cecconi, Mohsin M. Naqvi, Julian D. Gillmore, Philip N. Hawkins, Fabrizio Chiti, Ranieri Rolandi, Graham W. Taylor, Mark B. Pepys, Monica Stoppini and Vittorio Bellotti. Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin: ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN. J. Biol. Chem. 2013; 288, 30917–30930. © the American Society for Biochemistry and Molecular Biology

Systemic amyloidosis is a fatal disease caused by misfolding of native globular proteins, which then aggregate extracellularly as insoluble fibrils, damaging the structure and function of affected organs. The formation of amyloid fibrils in vivo is poorly understood. We recently identified the first naturally occurring structural variant, D76N, of human β2-microglobulin (β2m), the ubiquitous light chain of class I major histocompatibility antigens, as the amyloid fibril protein in a family with a new phenotype of late onset fatal hereditary systemic amyloidosis. Here we show that, uniquely, D76N β2m readily forms amyloid fibrils in vitro under physiological extracellular conditions. The globular native fold transition to the fibrillar state is primed by exposure to a hydrophobic-hydrophilic interface under physiological intensity shear flow. Wild type β2m is recruited by the variant into amyloid fibrils in vitro but is absent from amyloid deposited in vivo. This may be because, as we show here, such recruitment is inhibited by chaperone activity. Our results suggest general mechanistic principles of in vivo amyloid fibrillogenesis by globular proteins, a previously obscure process. Elucidation of this crucial causative event in clinical amyloidosis should also help to explain the hitherto mysterious timing and location of amyloid deposition.

71279

Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin : ROLES OF SHEAR FLOW, HYDROPHOBIC SURFACES, AND α-CRYSTALLIN

American Society for Biochemistry and Molecular Biology

英語

2013-10

Journal of Biological Chemistry

288

43

30917

30930

https://doi.org/10.1074/jbc.M113.498857

https://hdl.handle.net/11094/71279