Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor

Sanjay K. Mishra, Peter A. Keyel, Matthew J. Hawryluk, Nicole R. Agostinelli, Simon C. Watkins, Linton M. Traub

Research output: Contribution to journalArticle

235 Scopus citations

Abstract

Clathrin-coated pits at the cell surface select material for transportation into the cell interior. A major mode of cargo selection at the bud site is via the μ2 subunit of the AP-2 adaptor complex, which recognizes tyrosine-based internalization signals. Other internalization motifs and signals, including phosphorylation and ubiquitylation, also tag certain proteins for incorporation into a coated vesicle, but the mechanism of selection is unclear. Disabled-2 (Dab2) recognizes the FXNPXY internalization motif in LDL-receptor family members via an N-terminal phosphotyrosine-binding (PTB) domain. Here, we show that in addition to binding AP-2, Dab2 also binds directly to phosphoinositides and to clathrin, assembling triskelia into regular polyhedral coats. The FXNPXY motif and phosphoinositides contact different regions of the PTB domain, but can stably anchor Dab2 to the membrane surface, while the distal AP-2 and clathrin-binding determinants regulate clathrin lattice assembly. We propose that Dab2 is a typical member of a growing family of cargo-specific adaptor proteins, including β-arrestin, AP180, epsin, HIP1 and numb, which regulate clathrin-coat assembly at the plasma membrane by synchronizing cargo selection and lattice polymerization events.

Original languageEnglish
Pages (from-to)4915-4926
Number of pages12
JournalEMBO Journal
Volume21
Issue number18
DOIs
StatePublished - Sep 16 2002

Keywords

  • Cargo selection
  • Clathrin
  • Disabled-2
  • Phosphoinositide
  • Receptor-mediated endocytosis

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