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

ACS Chem Neurosci. 2019 Mar 20;10(3):1488-1496. doi: 10.1021/acschemneuro.8b00491. Epub 2018 Nov 28.


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 (HTB1M2). HTB1M2 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 HTB1M2 a potential therapeutic lead in the development of AD-targeted drugs and a tool for elucidating conformational changes in the Aβ42 peptide.

Keywords: Alzheimer’s disease; Aβ42 peptide; amyloids; directed evolution; neurodegeneration; neuronal cell toxicity; protein aggregation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity*
  • Cell Line, Tumor
  • Extracellular Fluid / drug effects
  • Extracellular Fluid / metabolism*
  • Genetic Engineering / methods*
  • Humans
  • Intracellular Fluid / drug effects
  • Intracellular Fluid / metabolism*
  • Peptide Fragments / genetics
  • Peptide Fragments / metabolism*
  • Peptide Fragments / toxicity*
  • Protein Aggregates / drug effects
  • Protein Aggregates / physiology*
  • Protein Domains / drug effects
  • Protein Domains / physiology
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • Amyloid beta-Peptides
  • HTB1 protein, S cerevisiae
  • Peptide Fragments
  • Protein Aggregates
  • Saccharomyces cerevisiae Proteins
  • amyloid beta-protein (1-42)