Evolutionary Changes on the Way to Clathrin-Mediated Endocytosis in Animals

Genome Biol Evol. 2016 Feb 12;8(3):588-606. doi: 10.1093/gbe/evw028.


Endocytic pathways constitute an evolutionarily ancient system that significantly contributed to the eukaryotic cell architecture and to the diversity of cell type-specific functions and signaling cascades, in particular of metazoans. Here we used comparative proteomic studies to analyze the universal internalization route in eukaryotes, clathrin-mediated endocytosis (CME), to address the issues of how this system evolved and what are its specific features. Among 35 proteins crucially required for animal CME, we identified a subset of 22 proteins common to major eukaryotic branches and 13 gradually acquired during evolution. Based on exploration of structure-function relationship between conserved homologs in sister, distantly related and early diverged branches, we identified novel features acquired during evolution of endocytic proteins on the way to animals: Elaborated way of cargo recruitment by multiple sorting proteins, structural changes in the core endocytic complex AP2, the emergence of the Fer/Cip4 homology domain-only protein/epidermal growth factor receptor substrate 15/intersectin functional complex as an additional interaction hub and activator of AP2, as well as changes in late endocytic stages due to recruitment of dynamin/sorting nexin 9 complex and involvement of the actin polymerization machinery. The evolutionary reconstruction showed the basis of the CME process and its subsequent step-by-step development. Documented changes imply more precise regulation of the pathway, as well as CME specialization for the uptake of specific cargoes and cell type-specific functions.

Keywords: clathrin-associated sorting proteins; dynamin/SNX9 complex; endocytic protein interaction network; evolution of endocytic system; regulation of AP2 conformational switch; scaffolding FCHO/Eps15/ITSN complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Clathrin / genetics*
  • Endocytosis / genetics*
  • Eukaryota / genetics
  • Evolution, Molecular*
  • Genetic Variation
  • Phylogeny
  • Proteins / genetics*
  • Proteomics
  • Structure-Activity Relationship


  • Clathrin
  • Proteins