Conformational Switching in PolyGln Amyloid Fibrils Resulting from a Single Amino Acid InsertionShow others and affiliations
2014 (English)In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 10, p. 2134-2142Article in journal (Refereed) Published
Abstract [en]
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 β-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-β 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 β-structure model for PolyQKd-33 and a model with two β-solenoid protofibrils for PolyQKd-32. These data provide evidence for β-arch-containing structures in polyglutamine fibrils and open future possibilities for structure-based drug design.
Place, publisher, year, edition, pages
2014. Vol. 106, no 10, p. 2134-2142
National Category
Physical Chemistry
Research subject
Chemistry of Interfaces
Identifiers
URN: urn:nbn:se:ltu:diva-3196DOI: 10.1016/j.bpj.2014.03.047ISI: 000336353200008PubMedID: 24853742Scopus ID: 2-s2.0-84901262053Local ID: 0fd7d673-773e-4079-a8e7-f810580b537fOAI: oai:DiVA.org:ltu-3196DiVA, id: diva2:976052
Note
Validerad; 2014; 20140527 (andbra)
2016-09-292016-09-292023-09-05Bibliographically approved