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| Subject Categories: Membranes & Transport |
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| The EMBO Journal
(2002) 21, 4915–4926, doi: 10.1093/emboj/cdf487 |
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| Disabled-2 exhibits the properties of a cargo-selective endocytic clathrin adaptor |
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| Sanjay K. Mishra1, 2, Peter A. Keyel1, 2, Matthew J. Hawryluk1, 2, Nicole R. Agostinelli1, 2, Simon C. Watkins1 and Linton M. Traub1 |
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1 Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace Street, S325BST, Pittsburgh, PA 15261, USA 2 S.K.Mishra, P.A.Keyel, M.J.Hawryluk and N.R.Agostinelli contributed equally to this work To whom correspondence should be addressed Linton M. Traub, traub+@pitt.edu Received 8 April 2002; Revised 19 July 2002; Accepted 29 July 2002. |
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| Abstract |
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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  2 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  -arrestin, AP180, epsin, HIP1 and numb, which regulate clathrin-coat assembly at the plasma membrane by synchronizing cargo selection and lattice polymerization events. |
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| Keywords: cargo selection, clathrin, Disabled-2, phosphoinositide, receptor-mediated endocytosis |
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