Stonin 2 is an AP-2-dependent endocytic sorting adaptor for synaptotagmin internalization and recycling.
Clathrin-mediated endocytosis is involved in the internalization, recycling, and degradation of cycling membrane receptors as well as in the biogenesis of synaptic vesicle proteins. While many constitutively internalized cargo proteins are recognized directly by the clathrin adaptor complex AP-2, stimulation-dependent endocytosis of membrane proteins is often facilitated by specialized sorting adaptors. Although clathrin-mediated endocytosis appears to be a major pathway for presynaptic vesicle cycling, no sorting adaptor dedicated to synaptic vesicle membrane protein endocytosis has been indentified in mammals. Here, we show that stonin 2, a mammalian ortholog of Drosophila stoned B, facilitates clathrin/AP-2-dependent internalization of synaptotagmin and targets it to a recycling vesicle pool in living neurons. The ability of stonin 2 to facilitate endocytosis of synaptotagmin is dependent on its association with AP-2, an intact mu-homology domain, and functional AP-2 heterotetramers. Our data identify stonin 2 as an AP-2-dependent endocytic sorting adaptor for synaptotagmin internalization and recycling.
Diril
M Kasim
MK
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Department of Membrane Biochemistry, Takustrasse 6, D-14195 Berlin, Germany.
Wienisch
Martin
M
Jung
Nadja
N
Klingauf
Jürgen
J
Haucke
Volker
V
D033962:Adaptor Protein Complex 2 / Q000235:genetics / Q000378:metabolism*; D033983:Adaptor Protein Complex mu Subunits / Q000235:genetics / Q000378:metabolism; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D017208:Rats, Wistar; D017386:Sequence Homology, Amino Acid; D050863:Synaptotagmin I / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
D033962:Adaptor Protein Complex 2; D033983:Adaptor Protein Complex mu Subunits; D033942:Adaptor Proteins, Vesicular Transport; D008565:Membrane Proteins; C429267:STON2 protein, human; C576989:Ston2 protein, rat; D050863:Synaptotagmin I; D033921:Vesicular Transport Proteins; C438886:adaptor protein complex 2, mu 2 subunit; D050857:Synaptotagmins