Mangione, PP;
Esposito, G;
Relini, A;
Raimondi, S;
Porcari, R;
Giorgetti, S;
Corazza, A;
... Bellotti, V; + view all
(2013)
Structure, folding dynamics and amyloidogenesis of Asp76Asn β2-microglobulin: roles of shear flow, hydrophobic surfaces and α crystallin.
Journal of Biological Chemistry
, 288
(43)
30917- 30930.
10.1074/jbc.M113.498857.
![[thumbnail of J._Biol._Chem.-2013-Mangione-30917-30.pdf]](https://discovery.ucl.ac.uk/style/images/fileicons/application_pdf.png) |
PDF
J._Biol._Chem.-2013-Mangione-30917-30.pdf Access restricted to UNSPECIFIED Download (4MB) |
Abstract
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, Asp76Asn, 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, Asp76Asn 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.
| Type: | Article |
|---|---|
| Title: | Structure, folding dynamics and amyloidogenesis of Asp76Asn β2-microglobulin: roles of shear flow, hydrophobic surfaces and α crystallin |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1074/jbc.M113.498857 |
| Publisher version: | http://dx.doi.org/10.1074/jbc.M113.498857 |
| Language: | English |
| Additional information: | This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
| Keywords: | Amyloid, Asp76Asn β2-microglobulin, Protein aggregation, Protein misfolding, Protein stability, Shear stress, chaperones, systemic amyloidosis |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1404530 |
Archive Staff Only
 |
View Item |
