AP-2 directly binds some endocytic cargo

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Reaction [binding]
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
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

Leicht, K, Briese, S, Schmidt, U, Joost, HG, Schürmann, A, Al-Hasani, H

J. Cell. Sci. 2006
21995445 Dab2 is a key regulator of endocytosis and post-endocytic trafficking of the cystic fibrosis transmembrane conductance regulator

Fu, L, Bebok, Z, Rowe, SM, Rab, A, Tang, LP, Collawn, JF

Biochem. J. 2012
18032517 A diacidic motif in human immunodeficiency virus type 1 Nef is a novel determinant of binding to AP-2

Hurley, JH, Chaudhuri, R, Lindwasser, OW, Smith, WJ, Yang, P, Bonifacino, JS

J. Virol. 2008
1317852 Characterization of the signal for rapid internalization of the bovine mannose 6-phosphate/insulin-like growth factor-II receptor

Jadot, M, Gregory, W, Kornfeld, S, Canfield, WM

J. Biol. Chem. 1992
26403691 Forty Years of Clathrin-coated Vesicles

Robinson, MS

Traffic 2015
16903783 Role of the AP2 beta-appendage hub in recruiting partners for clathrin-coated vesicle assembly

McMahon, HT, Ford, MG, Praefcke, GJ, Benmerah, A, Burtey, A, Peak-Chew, SY, Schmid, EM, Mills, IG

PLoS Biol. 2006
3417785 Deep-etch visualization of proteins involved in clathrin assembly

Heuser, JE, Keen, J

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

Lee, I, Kornfeld, S, Knisely, J, Bu, G, Doray, B

Mol. Biol. Cell 2007
2890644 Clathrin assembly proteins: affinity purification and a model for coat assembly

Keen, JH

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

Hurley, JH, Chaudhuri, R, Lindwasser, OW, Smith, WJ, Bonifacino, JS

J. Virol. 2007
16516836 Molecular switches involving the AP-2 beta2 appendage regulate endocytic cargo selection and clathrin coat assembly

Steinhauser, AL, Keyel, PA, Edeling, MA, Owen, DJ, Heuser, JE, Mishra, SK, Traub, LM, Collins, BM, Roth, R

Dev. Cell 2006
9812899 A structural explanation for the recognition of tyrosine-based endocytotic signals

Owen, DJ, Evans, PR

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

Storch, S, Braulke, T

J. Biol. Chem. 2001
24186068 Cargo recognition in clathrin-mediated endocytosis

Traub, LM, Bonifacino, JS

Cold Spring Harb Perspect Biol 2013
15473838 Adaptors for clathrin coats: structure and function

Owen, DJ, Collins, BM, Evans, PR

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

Mooseker, M, Hegan, P, Ameen, N, Collaco, A, Jakab, R

J. Biol. Chem. 2010
2257624 Transferrin receptor internalization sequence YXRF implicates a tight turn as the structural recognition motif for endocytosis

Tainer, JA, Collawn, JF, Jing, SQ, Esekogwu, V, Kuhn, LA, Stangel, M, Trowbridge, IS

Cell 1990
17713526 Integrating molecular and network biology to decode endocytosis

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
7569928 Interaction of tyrosine-based sorting signals with clathrin-associated proteins

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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