AP180 couples protein retrieval to clathrin-mediated endocytosis of synaptic vesicles.
How clathrin-mediated endocytosis (CME) retrieves vesicle proteins into newly formed synaptic vesicles (SVs) remains a major puzzle. Besides its roles in stimulating clathrin-coated vesicle formation and regulating SV size, the clathrin assembly protein AP180 has been identified as a key player in retrieving SV proteins. The mechanisms by which AP180 recruits SV proteins are not fully understood. Here, we show that following acute inactivation of AP180 in Drosophila, SV recycling is severely impaired at the larval neuromuscular synapse based on analyses of FM 1-43 uptake and synaptic ultrastructure. More dramatically, AP180 activity is important to maintain the integrity of SV protein complexes at the plasma membrane during endocytosis. These observations suggest that AP180 normally clusters SV proteins together during recycling. Consistent with this notion, SV protein composition and distribution are altered in AP180 mutant flies. Finally, AP180 co-immunoprecipitates with SV proteins, including the vesicular glutamate transporter and neuronal synaptobrevin. These results reveal a new mode by which AP180 couples protein retrieval to CME of SVs. AP180 is also genetically linked to Alzheimer's disease. Hence, the findings of this study may provide new mechanistic insight into the role of AP180 dysfunction in Alzheimer's disease.
Department of Biology, University of Oklahoma, Norman, OK, 73019, USA.
Phillip A
PA
Vanlandingham
Mojgan Padash
MP
Barmchi
Suzanne
S
Royer
Rebekah
R
Green
Hong
H
Bao
Noreen
N
Reist
Bing
B
Zhang
D000818:Animals; D002966:Clathrin / Q000502:physiology*; D004330:Drosophila; D004705:Endocytosis / Q000502:physiology*; D005089:Exocytosis; D034041:Monomeric Clathrin Assembly Proteins / Q000502:physiology*; D011485:Protein Binding; D013572:Synaptic Vesicles / Q000502:physiology*; D019076:Transgenes
D002966:Clathrin; D034041:Monomeric Clathrin Assembly Proteins; C439023:clathrin assembly protein AP180
AP180; Drosophila; clathrin; endocytosis; exocytosis; synaptic vesicles; synaptobrevin; synaptotagmin; vesicular glutamate transporter