Conformational switching in PolyGln amyloid fibrils resulting from a single amino acid insertion.
Biophys J
; 106(10): 2134-42, 2014 May 20.
Article
em En
| MEDLINE
| ID: mdl-24853742
ABSTRACT
The established correlation between neurodegenerative disorders and intracerebral deposition of polyglutamine aggregates motivates attempts to better understand their fibrillar structure. We designed polyglutamines with a few lysines inserted to overcome the hindrance of extreme insolubility and two D-lysines to limit the lengths of ß-strands. One is 33 amino acids long (PolyQKd-33) and the other has one fewer glutamine (PolyQKd-32). Both form well-dispersed fibrils suitable for analysis by electron microscopy. Electron diffraction confirmed cross-ß structures in both fibrils. Remarkably, the deletion of just one glutamine residue from the middle of the peptide leads to substantially different amyloid structures. PolyQKd-32 fibrils are consistently 10-20% wider than PolyQKd-33, as measured by negative staining, cryo-electron microscopy, and scanning transmission electron microscopy. Scanning transmission electron microscopy analysis revealed that the PolyQKd-32 fibrils have 50% higher mass-per-length than PolyQKd-33. This distinction can be explained by a superpleated ß-structure model for PolyQKd-33 and a model with two ß-solenoid protofibrils for PolyQKd-32. These data provide evidence for ß-arch-containing structures in polyglutamine fibrils and open future possibilities for structure-based drug design.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Peptídeos beta-Amiloides
/
Substituição de Aminoácidos
/
Multimerização Proteica
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article