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Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition |
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| Authors: | von Kleist Lisa Stahlschmidt Wiebke Bulut Haydar Gromova Kira Puchkov Dmytro Robertson Mark J MacGregor Kylie A Tomilin Nikolay Tomlin Nikolay Pechstein Arndt Chau Ngoc Chircop Megan Sakoff Jennette von Kries Jens Peter Saenger Wolfram Kräusslich Hans-Georg Shupliakov Oleg Robinson Phillip J McCluskey Adam Haucke Volker |
| Institution: | 1 Institute of Chemistry and Biochemistry & Neurocure Cluster of Excellence, Freie Universität Berlin, 14195 Berlin, Germany 2 Centre for Chemical Biology, Chemistry, The University of Newcastle, Callaghan NSW 2308, Australia 3 Department of Neuroscience, DBRM, Karolinska Institutet, 17117 Stockholm, Sweden 4 Cell Signalling Unit, Children's Medical Research Institute, The University of Sydney, Sydney NSW 2145, Australia 5 Department of Medical Oncology, Calvary Mater Newcastle Hospital, Waratah NSW 2298, Australia 6 Leibniz-Institut für Molekulare Pharmakologie (FMP), 13125 Berlin-Buch, Germany 7 Department of Infectious Diseases, Virology, University of Heidelberg, 69120 Heidelberg, Germany |
| Abstract: | Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling. |
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