De novo design of a biologically active amyloid

Science. 2016 Nov 11;354(6313):aah4949. doi: 10.1126/science.aah4949.

Abstract

Most human proteins possess amyloidogenic segments, but only about 30 are associated with amyloid-associated pathologies, and it remains unclear what determines amyloid toxicity. We designed vascin, a synthetic amyloid peptide, based on an amyloidogenic fragment of vascular endothelial growth factor receptor 2 (VEGFR2), a protein that is not associated to amyloidosis. Vascin recapitulates key biophysical and biochemical characteristics of natural amyloids, penetrates cells, and seeds the aggregation of VEGFR2 through direct interaction. We found that amyloid toxicity is observed only in cells that both express VEGFR2 and are dependent on VEGFR2 activity for survival. Thus, amyloid toxicity here appears to be both protein-specific and conditional-determined by VEGFR2 loss of function in a biological context in which target protein function is essential.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amyloid / chemistry*
  • Amyloid / metabolism
  • Amyloidosis / chemically induced
  • Amyloidosis / metabolism*
  • Animals
  • HEK293 Cells
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Mice
  • Peptide Fragments / chemical synthesis
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity
  • Peptides / chemistry*
  • Peptides / metabolism
  • Peptides / toxicity
  • Protein Aggregation, Pathological / chemically induced
  • Protein Aggregation, Pathological / metabolism*
  • Protein Sorting Signals
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors
  • Vascular Endothelial Growth Factor Receptor-2 / chemistry
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Amyloid
  • Intercellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Peptides
  • Protein Sorting Signals
  • vascin
  • Vascular Endothelial Growth Factor Receptor-2