Regulation of Clathrin-Mediated Endocytosis - PubMed (original) (raw)

Review

Regulation of Clathrin-Mediated Endocytosis

Marcel Mettlen et al. Annu Rev Biochem. 2018.

Abstract

Clathrin-mediated endocytosis (CME) is the major endocytic pathway in mammalian cells. It is responsible for the uptake of transmembrane receptors and transporters, for remodeling plasma membrane composition in response to environmental changes, and for regulating cell surface signaling. CME occurs via the assembly and maturation of clathrin-coated pits that concentrate cargo as they invaginate and pinch off to form clathrin-coated vesicles. In addition to the major coat proteins, clathrin triskelia and adaptor protein complexes, CME requires a myriad of endocytic accessory proteins and phosphatidylinositol lipids. CME is regulated at multiple steps-initiation, cargo selection, maturation, and fission-and is monitored by an endocytic checkpoint that induces disassembly of defective pits. Regulation occurs via posttranslational modifications, allosteric conformational changes, and isoform and splice-variant differences among components of the CME machinery, including the GTPase dynamin. This review summarizes recent findings on the regulation of CME and the evolution of this complex process.

Keywords: AP2; adaptor protein-2; dynamin; endocytic accessory proteins; endocytic checkpoint; evolution; signaling.

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Figures

Figure 1

Figure 1

Clathrin-mediated endocytosis is regulated by multiple factors at multiple stages. Clathrin-mediated endocytosis is a multistage process involving the initiation and stabilization of nascent CCPs, maturation and curvature generation, and finally dynamin-catalyzed fission. Each step is regulated by multiple inputs. Abbreviations: AAK1, adaptor associated kinase 1; AP2, adaptor protein-2; EAPs, endocytic accessory proteins; PIP, phosphatidylinositol phosphate. Figure modified from Schmid (107).

Figure 2

Figure 2

The central role of AP2 in regulating CCP initiation and stabilization. (a) The allosteric regulation of AP2 conformational changes controls early steps in CME, including: (❶) the recruitment of cytosolic AP2 in the closed conformation to the PM, where (❷) PI4,5P2 binding releases the β2 hinge to nucleate clathrin assembly; (❸) cargo and PI4,5P2 binding to the μ2 subunit, as well as interactions with EAPs, trigger the open conformation to stabilize the growing, nascent CCP and prevent early abortive events; (❹) sustained PI4,5P2 interactions with α, β2, and μ2 binding sites, as well as clathrin-stimulated AAK1 phosphorylation of μ2, supports further cargo recruitment, CCP growth, and (❺) maturation. Boxes correspond to sequential AP2 conformational changes enlarged in panel b. (b) Sequential interactions between PI4,5P2 and α, β2, and μ2 subunits, as well as with pioneer EAPs, trigger and stabilize conformational changes that activate AP2. AAK1, which phosphorylates μ2 to stabilize the open conformation, is activated by assembled clathrin, thus providing a positive feedback loop during CCP maturation. Abbreviations: AAK1, adaptor associated kinase 1; AP2, adaptor protein-2; CALM, clathrin assembly lymphoid myeloid leukemia; CCP, clathrin-coated pit; CME, clathrin-mediated endocytosis; EAPs, endocytic accessory proteins; Eps15, EGF-receptor substrate 15; FCHo, Fer/Cip4 homology domain-only protein; NECAP, adaptin-ear-binding coat-associated protein; PI4,5P2, phosphatidylinositol lipid; PM, plasma membrane.

Figure 3

Figure 3

The endocytic checkpoint hypothesis. A hypothetical endocytic checkpoint monitors the fidelity of CCP maturation. Deficiencies in several endocytic accessory proteins lead to decreased efficiency of CCP maturation and increased rates of turnover of abortive CCPs. Small interfering RNA-mediated knockdown of dynamin-2 decreases the rate of abortive CCP turnover. Based on these data, we speculate that the properties of nascent CCPs, such as coat assembly, curvature generation, and cargo concentration, are monitored by SH3 domain-containing dynamin binding partners that also interact with coat components, cargo, and/or sense curvature and kinetically control dynamin assembly. Together, these interactions function to monitor the fidelity of CCP maturation. Much remains to be done to test this hypothesis and to identify components of the endocytic checkpoint apparatus and the mechanisms to sense and turnover aberrant CCP intermediates. Abbreviations: AD, appendage domain; AP2, adaptor protein-2; CALM, clathrin assembly lymphoid myeloid leukemia; CCP, clathrin-coated pit; CCV, clathrin-coated vesicle; CLCs, clathrin light chains; SH3, Src-homology domain 3; TfnR, transferrin receptor. Figure modified from Schmid (107).

Figure 4

Figure 4

Regulation of dynamin by posttranslational modifications, intramolecular interactions, and splice variants. The GTPase dynamin consists of five functional domains and exists as a tetramer in solution (PDB ID 53AF; 152). Dynamin is regulated by: (a) phosphorylation of the PRD, which modulates SH3 domain binding; (b) SH3 domain-containing partners that bind the PRD and can either stimulate or inhibit dynamin assembly and/or GTPase activity; (c) intramolecular interactions between the PHD and stalk that prevent higher order assembly; and (d) splice variants within the PRD that alter interactions with kinases or phosphatases or splice variants within the middle domain that affect allosteric conformational changes and modulate the effects of SH3 domain interactions on dynamin assembly. Dynamin is a key regulator of CME; therefore, regulation of dynamin can impact multiple stages of CME. Abbreviations: CME, clathrin-mediated endocytosis; GED, GTPase effector domain; PDB, Protein Data Bank; PHD, pleckstrin homology domain; PRD, proline/arginine-rich domain; SH3, Src-homology 3 domain.

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References

    1. Conner SD, Schmid SL. 2002. Identification of an adaptor-associated kinase, AAK1, as a regulator of clathrin-mediated endocytosis. J. Cell Biol 156:921–29 - PMC - PubMed
    1. Robinson MS. 2015. Forty years of clathrin-coated vesicles. Traffic 16:1210–38 - PubMed
    1. Schmid EM, McMahon HT. 2007. Integrating molecular and network biology to decode endocytosis. Nature 448:883–88 - PubMed
    1. Antonny B, Burd C, De Camilli P, Chen E, Daumke O, et al. 2016. Membrane fission by dynamin: what we know and what we need to know. EMBO J. 35:2270–84 - PMC - PubMed
    1. Morlot S, Roux A. 2013. Mechanics of dynamin-mediated membrane fission. Annu. Rev. Biophys 42:629–49 - PMC - PubMed

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