Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition

von Kleist, Lisa, Stahlschmidt, Wiebke, Bulut, Haydar, Gromova, Kira, Puchkov, Dmytro, Robertson, Mark J., MacGregor, Kylie A., 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, and Haucke, Volker (2011) Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. Cell, 146 (3). pp. 471-484.

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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.

Item ID: 36829
Item Type: Article (Refereed Research - C1)
ISSN: 1097-4172
Funders: Deutsche Forschungsgemeinschaft (DFG), European Science Foundation, Swedish Research Council
Projects and Grants: (FOR 806-HA2686/3-1,3-2; SFB765/B4; Exc-257), European Science Foundation (Euromembrane-HA2686/6-1), Swedish Research Council (13473 and 20587)
Date Deposited: 10 Dec 2014 07:31
FoR Codes: 03 CHEMICAL SCIENCES > 0305 Organic Chemistry > 030503 Organic Chemical Synthesis @ 100%
SEO Codes: 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 50%
97 EXPANDING KNOWLEDGE > 970106 Expanding Knowledge in the Biological Sciences @ 50%
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