Angiopoietins have distinct modular domains essential for receptor binding, dimerization and superclustering

Nat Struct Biol. 2003 Jan;10(1):38-44. doi: 10.1038/nsb880.


Angiopoietins are a recently discovered family of angiogenic factors that interact with the endothelial receptor tyrosine kinase Tie2, either as agonists (angiopoietin-1) or as context-dependent agonists/antagonists (angiopoietin-2). Here we show that angiopoietin-1 has a modular structure unlike any previously characterized growth factor. This modular structure consists of a receptor-binding domain, a dimerization motif and a superclustering motif that forms variable-sized multimers. Genetic engineering of precise multimers of the receptor-binding domain of angiopoietin-1, using surrogate multimerization motifs, reveals that tetramers are the minimal size required for activating endothelial Tie2 receptors. In contrast, engineered dimers can antagonize endothelial Tie2 receptors. Surprisingly, angiopoietin-2 has a modular structure and multimerization state similar to that of angiopoietin-1, and its antagonist activity seems to be a subtle property encoded in its receptor-binding domain.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Angiopoietin-1 / chemistry
  • Angiopoietin-1 / genetics
  • Angiopoietin-1 / metabolism
  • Angiopoietin-2 / chemistry
  • Angiopoietin-2 / genetics
  • Angiopoietin-2 / metabolism
  • Angiopoietins / chemistry*
  • Angiopoietins / genetics
  • Angiopoietins / metabolism*
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Dimerization
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Models, Molecular
  • Phosphorylation
  • Protein Binding
  • Protein Engineering
  • Receptor, TIE-2 / metabolism*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism


  • Angiopoietin-1
  • Angiopoietin-2
  • Angiopoietins
  • Recombinant Proteins
  • Receptor, TIE-2