ClathrinAP2Dependent Endocytosis A Novel Playground for the Pharmacological Toolbox

Contents

1 Introduction 106

2 Steps of Clathrin/AP-2-Mediated Endocytosis 107

3 AP-2: A Member of the AP-Complex Family 108

4 Getting AP-2 to the Plasma Membrane: The Role of Phosphoinositides 111

5 AP-2 Interactions with Cargo 111

6 AP-2 as a Recruiter of Clathrin 113

7 Binding of Accessory Endocytic Proteins to AP-2 Appendage Domains 114

7.1 Interaction Sites Within the a-Appendage Domain 114

7.2 Interaction Sites Within the a2-Appendage Domain 114

8 AP-2-Binding Accessory Proteins Defining Cargo-Selective Pathways 115

9 Pharmacological Inhibition of Clathrin/AP-2-Mediated Endocytosis 116

9.1 Inhibition by Cytosolic Acidification 116

9.2 K+ Depletion 116

9.3 Chlorpromazine 117

9.4 High Sucrose 117

9.5 Dynasore 117

10 Perspective 118

References 118

Abstract Endocytosis is a vital process for mammalian cells by which they communicate with their environment, internalize nutrients, hormones, or growth factors, or take up extracellular fluids and particles. The best studied among the various pathways to ingest material from the extracellular side is clathrin/AP-2-mediated endocytosis. The past several years have allowed us to gain unprecedented molecular insights into the role of the heterotetrameric AP-2 adaptor complex as a central protein-protein and protein-lipid interaction hub at the plasmalemma. During the initial stages of clathrin-coated pit formation, AP-2 interacts with phosphoinositides and cargo membrane proteins as well as with a variety of accessory proteins and

V. Haucke

Institute of Chemistry and Biochemistry, Department of Membrane Biochemistry, Freie Universität Berlin, Takustraße 6, 14195 Berlin, Germany v. [email protected]

E. Klussmann, J. Scott (eds.) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology 186, © Springer-Verlag Berlin Heidelberg 2008

clathrin to coordinate clathrin coat polymerization with membrane deformation and cargo recruitment. In addition, a growing list of alternative adaptors provides opportunity for clathrin-dependent cargo selective pathways of internalization and endosomal sorting. Many of these interactions are now understood in structural detail and are thus amenable to pharmacological interference. In this review we will summarize our present state of knowledge about AP-2 and its partners in endocyto-sis and delineate potential strategies for pharmacological manipulations.

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