Reactome: A Curated Pathway Database

Initial binding of AP-2 and clathrin to PI(4,5)P2

Stable Identifier
Homo sapiens
Locations in the PathwayBrowser

Assembly of an endocytic clathrin-coated pit (CCP) at the plasma membrane depends on the recruitment of the AP-2 adaptor protein complex and clathrin triskelions to the lipid bilayer (reviewed in McMahon and Boucrot, 2011; Robinson, 2015). Transient interactions between the plasma membrane-enriched lipid phosphatidlyinositol 4,5-bisphosphate (PI(4,5)P2) and AP-2 initiate coated pit formation (Beck et al, 1991; Honing et al, 2005; Loerke et al, 2009; Cocucci et al, 2012). A proportion of the transient complexes between AP-2, clathrin and the plasma membrane are rapidly stabilized by the recruitment of a number of proteins, including FCHo proteins, intersectins (ITSNs), EPS15 and SGIP1 among others (Henne et al, 2010; Stimpson et al, 2009; Reider et al, 2009; Cocucci et al, 2012; reviewed in McMahon and Boucrot, 2011). Many of these early players in CCP formation bind both to the plasma membrane and to the AP-2 complex and/or clathrin.

CCP formation is a highly heterogeneous and dynamic process and includes abortive initiation of nearly half of nascent CCPs (Loerke et al, 2009; Aguet et al, 2013). Heterogeneity is in part the result of the widely varied cargo proteins, which compete for a limited number of interaction hubs on AP-2 and clatrhin and influence the other protein components of the CCPs. Heterogeneity may also be partly stochastic, or be influenced by the presence of CCP 'hot spots' in the plasma membrane (Taylor et al, 2011; Antonescu et al, 2011; Gaidarov et al, 1999; Ehrlich et al, 2004; Saffarian et al, 2009; Nunez et al, 2011). It is important to note that although events in this pathway are depicted as occuring sequentially in a defined order, in reality the assembly of a clathrin-coated vesicle may be highly variable and the temporal boundaries are likely less clearly defined. Moreover, not every CCP will have all of the proteins indicated in this pathway.

Literature References
PubMed ID Title Journal Year
21779028 Molecular mechanism and physiological functions of clathrin-mediated endocytosis Nat. Rev. Mol. Cell Biol. 2011
1847920 Interaction of phosphoinositide cycle intermediates with the plasma membrane-associated clathrin assembly protein AP-2 J. Biol. Chem. 1991
15339664 Endocytosis by random initiation and stabilization of clathrin-coated pits Cell 2004
19809571 Distinct dynamics of endocytic clathrin-coated pits and coated plaques PLoS Biol. 2009
19296720 Cargo and dynamin regulate clathrin-coated pit maturation PLoS Biol. 2009
21883765 Hotspots organize clathrin-mediated endocytosis by efficient recruitment and retention of nucleating resources Traffic 2011
22863004 The first five seconds in the life of a clathrin-coated pit Cell 2012
26403691 Forty Years of Clathrin-coated Vesicles Traffic 2015
20448150 FCHo proteins are nucleators of clathrin-mediated endocytosis Science 2010
23891661 Advances in analysis of low signal-to-noise images link dynamin and AP2 to the functions of an endocytic checkpoint Dev. Cell 2013
21613550 Phosphatidylinositol-(4,5)-bisphosphate regulates clathrin-coated pit initiation, stabilization, and size Mol. Biol. Cell 2011
19776351 Early-arriving Syp1p and Ede1p function in endocytic site placement and formation in budding yeast Mol. Biol. Cell 2009
21445324 A high precision survey of the molecular dynamics of mammalian clathrin-mediated endocytosis PLoS Biol. 2011
10559856 Spatial control of coated-pit dynamics in living cells Nat. Cell Biol. 1999
19713939 Syp1 is a conserved endocytic adaptor that contains domains involved in cargo selection and membrane tubulation EMBO J. 2009
15916959 Phosphatidylinositol-(4,5)-bisphosphate regulates sorting signal recognition by the clathrin-associated adaptor complex AP2 Mol. Cell 2005
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