AP-2 directly binds some endocytic cargo

Stable Identifier
R-HSA-8866277
Type
Reaction [binding]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
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AP-2 is a heterotetrameric complex that was originally identified as a factor required to help assemble clathrin at the plasma membrane to promote endocytosis (Keen et al, 1987; reviewed in Robinson, 2015). In addition to its structural role, AP-2 also contributes to cargo recognition and recruitment through direct binding of tyrosine- and dileucine-based sorting motifs in the cytoplasmic tails of cargo such as the transferrin receptor, cation dependent and independent mannose-6-phosphate receptors, CFTR, CD3 and CD4 proteins, glucose transporters and the viral Nef protein, among many others (Collawn et al, 1990; Jadot et al, 1992; Storch and Braulke, 2001; Ohno et al, 1995; Letourneur and Klausner, 1992; Kelly et al, 2008; Schmidt et al, 2006; Doray et al, 2007; Chaudhuri et al, 2007; Lindwasser et al, 2008; Collaco et al, 2010; Fu et al, 2012; reviewed in Traub and Bonifacino, 2013). Both membrane recruitment and interaction of AP-2 with the sorting signals of cargo are mediated by the large 'trunk' domain of AP-2, made up of the medium and small subunits and the N-terminal domains of the 2 large subunits (Collins et al, 2002; Heuser and Keen, 1988; Owen and Evans, 1998; Kelly et al, 2008; reviewed in Traub and Bonifacino, 2013).

AP-2 also facilitates the recruitment of many other endocytic cargo indirectly by binding to CLASP proteins (clathrin associated sorting proteins) that themselves interact with cargo (Schmid et al, 2006; Edeling et al, 2006; reviewed in Traub and Bonifacino, 2013). CLASP proteins generally interact with AP-2 through the globular 'beta-2 ear', one of 2 ear domains made up of the C-terminal regions of the two large subunits (reviewed in Owen, 2004; Schmid and McMahon, 2007).

Literature References
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Biochem. J. 2012
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Traffic 2015
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Dev. Cell 2006
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Science 1998
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Owen, DJ, Collins, BM, Evans, PR

Annu. Rev. Cell Dev. Biol. 2004
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J. Biol. Chem. 2010
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Cell 1990
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McMahon, HT, Schmid, EM

Nature 2007
1535555 A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains

Klausner, RD, Letourneur, F

Cell 1992
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Fournier, MC, Miyatake, S, Ohno, H, Bonifacino, JS, Kirchhausen, T, Stewart, J, Rhee, I, Gallusser, A, Saito, T, Bosshart, H

Science 1995
12086608 Molecular architecture and functional model of the endocytic AP2 complex

Owen, DJ, Collins, BM, Kent, HM, McCoy, AJ, Evans, PR

Cell 2002
19140243 A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex

Kelly, BT, Miller, SE, Höning, S, Owen, DJ, Späte, K, McCoy, AJ, Evans, PR

Nature 2008
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