Structure, Folding Dynamics, and Amyloidogenesis of D76N β2-Microglobulin
| Autor: | Mark B. Pepys, Young-Ho Lee, Sofia Giorgetti, Palma Mangione, Alessandra Corazza, Ranieri Rolandi, Vittorio Bellotti, Graham W. Taylor, Julian D. Gillmore, Monica Stoppini, Fabrizio Chiti, Philip N. Hawkins, Riccardo Porcari, Annalisa Relini, Sara Raimondi, Hisashi Yagi, Amanda Penco, Gennaro Esposito, Federico Fogolari, Yuji Goto, Mohsin M. Naqvi, Ciro Cecconi |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Globular protein
macromolecular substances Protein aggregation 010402 general chemistry 01 natural sciences Biochemistry 03 medical and health sciences medicine Amyloid precursor protein Molecular Biology 030304 developmental biology chemistry.chemical_classification 0303 health sciences biology Chemistry Amyloidosis P3 peptide Fibrillogenesis Cell Biology medicine.disease 3. Good health 0104 chemical sciences Biochemistry of Alzheimer's disease Cell biology biology.protein Protein folding |
| Zdroj: | Journal of Biological Chemistry. 288:30917-30930 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|