Modulation of beta-amyloid aggregation by engineering the sequence connecting beta-strand forming domains

Yang Hu, Heqiu Zheng, Baihao Su, Michael Hernandez, Jin Ryoun Kim

Research output: Contribution to journalArticlepeer-review

Abstract

Aggregation of beta-amyloid (Aβ) into oligomers and fibrils is associated with the pathology of Alzheimer's disease. The major structural characteristics of Aβ fibrils include the presence of β sheet-loop-β sheet conformations. Several lines of study suggested a potentially important role of the Aβ loop forming sequence (referred to as the Aβ linker region) in Aβ aggregation. Effects of mutations in several charged residues within the Aβ linker region on aggregation have been extensively studied. However, little is known about oligomerization effects of sequence variation in other residues within the Aβ linker region. Moreover, modulation effects of the Aβ linker mutants on Aβ aggregation have yet to be characterized. Here, we created and characterized Aβ linker variants containing sequences preferentially found in specific β turn conformations. Our results indicate that a propensity to form oligomers may be changed by local sequence variation in the Aβ linker region without mutating the charged residues. Strikingly, one Aβ linker variant rapidly formed protofibrillar oligomers, which did not convert to fibrillar aggregates in contrast to Aβ aggregating to fibrils under similar incubation conditions. Moreover, our results suggest that molecular forces critical in oligomerization and fibrillization may differ at least for those involved in the linker region. When co-incubated with Aβ, some Aβ linker variants were found to induce accumulation of Aβ oligomers. Our results suggest that engineering of the Aβ linker region as described in this paper may represent a novel approach to control Aβ oligomerization and create Aβ oligomerization modulators.

Original languageEnglish (US)
Pages (from-to)1069-1079
Number of pages11
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Volume1824
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • Amyloid
  • Fibril
  • Oligomer
  • Protein aggregation
  • Protein design
  • Protein-protein interaction

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biophysics
  • Biochemistry
  • Molecular Biology

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