Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly

Dev Cell. 2006 Mar;10(3):329-42. doi: 10.1016/j.devcel.2006.01.016.


Clathrin-associated sorting proteins (CLASPs) expand the repertoire of endocytic cargo sorted into clathrin-coated vesicles beyond the transmembrane proteins that bind physically to the AP-2 adaptor. LDL and GPCRs are internalized by ARH and beta-arrestin, respectively. We show that these two CLASPs bind selectively to the AP-2 beta2 appendage platform via an alpha-helical [DE](n)X(1-2)FXX[FL]XXXR motif, and that this motif also occurs and is functional in the epsins. In beta-arrestin, this motif maintains the endocytosis-incompetent state by binding back on the folded core of the protein in a beta strand conformation. Triggered via a beta-arrestin/GPCR interaction, the motif must be displaced and must undergo a strand to helix transition to enable the beta2 appendage binding that drives GPCR-beta-arrestin complexes into clathrin coats. Another interaction surface on the beta2 appendage sandwich is identified for proteins such as eps15 and clathrin, suggesting a mechanism by which clathrin displaces eps15 to lattice edges during assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism*
  • Amino Acid Sequence
  • Arrestins / chemistry
  • Arrestins / genetics
  • Arrestins / metabolism
  • Binding Sites
  • Clathrin / metabolism*
  • Clathrin-Coated Vesicles / metabolism*
  • Crystallography, X-Ray
  • Endocytosis / physiology*
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides / genetics
  • Peptides / metabolism
  • Protein Binding
  • Protein Conformation*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary*
  • Receptors, G-Protein-Coupled / metabolism
  • Receptors, LDL / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Transcription Factor AP-2 / chemistry*
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism
  • Vesicular Transport Proteins / genetics
  • Vesicular Transport Proteins / metabolism
  • beta-Arrestins


  • Adaptor Proteins, Vesicular Transport
  • Arrestins
  • Clathrin
  • Peptides
  • Receptors, G-Protein-Coupled
  • Receptors, LDL
  • Recombinant Fusion Proteins
  • Transcription Factor AP-2
  • Vesicular Transport Proteins
  • beta-Arrestins
  • epsin

Associated data

  • PDB/2G30