Reactome: A Curated Pathway Database

AP-2 directly binds some endocytic cargo

Stable Identifier
Homo sapiens
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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
PubMed ID Title Journal Year
21995445 Dab2 is a key regulator of endocytosis and post-endocytic trafficking of the cystic fibrosis transmembrane conductance regulator Biochem. J. 2012
16723738 Endocytosis of the glucose transporter GLUT8 is mediated by interaction of a dileucine motif with the beta2-adaptin subunit of the AP-2 adaptor complex J. Cell. Sci. 2006
18032517 A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2 J. Virol. 2008
1317852 Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor J. Biol. Chem. 1992
26403691 Forty Years of Clathrin-coated Vesicles Traffic 2015
16903783 Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly PLoS Biol. 2006
3417785 Deep-etch visualization of proteins involved in clathrin assembly J. Cell Biol. 1988
17360967 The gamma/sigma1 and alpha/sigma2 hemicomplexes of clathrin adaptors AP-1 and AP-2 harbor the dileucine recognition site Mol. Biol. Cell 2007
2890644 Clathrin assembly proteins: affinity purification and a model for coat assembly J. Cell Biol. 1987
17267500 Downregulation of CD4 by human immunodeficiency virus type 1 Nef is dependent on clathrin and involves direct interaction of Nef with the AP2 clathrin adaptor J. Virol. 2007
16516836 Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly Dev. Cell 2006
9812899 A structural explanation for the recognition of tyrosine-based endocytotic signals Science 1998
11071885 Multiple C-terminal motifs of the 46-kDa mannose 6-phosphate receptor tail contribute to efficient binding of medium chains of AP-2 and AP-3 J. Biol. Chem. 2001
24186068 Cargo recognition in clathrin-mediated endocytosis Cold Spring Harb Perspect Biol 2013
15473838 Adaptors for clathrin coats: structure and function Annu. Rev. Cell Dev. Biol. 2004
20351096 Alpha-AP-2 directs myosin VI-dependent endocytosis of cystic fibrosis transmembrane conductance regulator chloride channels in the intestine J. Biol. Chem. 2010
2257624 Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis Cell 1990
17713526 Integrating molecular and network biology to decode endocytosis Nature 2007
1535555 A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains Cell 1992
7569928 Interaction of tyrosine-based sorting signals with clathrin-associated proteins Science 1995
12086608 Molecular architecture and functional model of the endocytic AP2 complex Cell 2002
19140243 A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex Nature 2008
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