An Engineered Variant of the B1 Domain of Protein G Suppresses the Aggregation and Toxicity of Intra- and Extracellular Aβ42

Victor Banerjee, Ofek Oren, Bar Dagan, Ran Taube, Stanislav Engel, Niv Papo

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Intra- and extraneuronal deposition of amyloid β (Aβ) peptides have been linked to Alzheimer's disease (AD). While both intra- and extraneuronal Aβ deposits affect neuronal cell viability, the molecular mechanism by which these Aβ structures, especially when intraneuronal, do so is still not entirely understood. This makes the development of inhibitors challenging. To prevent the formation of toxic Aβ structural assemblies so as to prevent neuronal cell death associated with AD, we used a combination of computational and combinatorial-directed evolution approaches to develop a variant of the HTB1 protein (HTB1 M2 ). HTB1 M2 inhibits in vitro self-assembly of Aβ42 peptide and shifts the Aβ42 aggregation pathway to the formation of oligomers that are nontoxic to neuroblastoma SH-SY5Y cells overexpressing or treated with Aβ42 peptide. This makes HTB1 M2 a potential therapeutic lead in the development of AD-targeted drugs and a tool for elucidating conformational changes in the Aβ42 peptide.

Original languageEnglish
Pages (from-to)1488-1496
Number of pages9
JournalACS Chemical Neuroscience
Volume10
Issue number3
DOIs
StatePublished - 20 Mar 2019

Keywords

  • Alzheimer's disease
  • Aβ42 peptide
  • amyloids
  • directed evolution
  • neurodegeneration
  • neuronal cell toxicity
  • protein aggregation

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