Molecular switches involving the AP-2 β2 appendage regulate endocytic cargo selection and clathrin coat assembly

Melissa A. Edeling, Sanjay K. Mishra, Peter A. Keyel, Amie L. Steinhauser, Brett M. Collins, Robyn Roth, John E. Heuser, David J. Owen, Linton M. Traub

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124 Scopus citations

Abstract

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 β-arrestin, respectively. We show that these two CLASPs bind selectively to the AP-2 β2 appendage platform via an α-helical [DE]nX1-2 FXX[FL]XXXR motif, and that this motif also occurs and is functional in the epsins. In β-arrestin, this motif maintains the endocytosis-incompetent state by binding back on the folded core of the protein in a β strand conformation. Triggered via a β-arrestin/ GPCR interaction, the motif must be displaced and must undergo a strand to helix transition to enable the β2 appendage binding that drives GPCR-β-arrestin complexes into clathrin coats. Another interaction surface on the β2 appendage sandwich is identified for proteins such as eps15 and clathrin, suggesting a mechanism by which clathrin displaces eps15 to lattice edges during assembly.

Original languageEnglish
Pages (from-to)329-342
Number of pages14
JournalDevelopmental Cell
Volume10
Issue number3
DOIs
StatePublished - Mar 2006

Keywords

  • Cell bio
  • Signaling

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    Edeling, M. A., Mishra, S. K., Keyel, P. A., Steinhauser, A. L., Collins, B. M., Roth, R., Heuser, J. E., Owen, D. J., & Traub, L. M. (2006). Molecular switches involving the AP-2 β2 appendage regulate endocytic cargo selection and clathrin coat assembly. Developmental Cell, 10(3), 329-342. https://doi.org/10.1016/j.devcel.2006.01.016