Author/Authors :
Lisa von Kleist، نويسنده , , Wiebke Stahlschmidt، نويسنده , , Haydar Bulut، نويسنده , , Kira Gromova، نويسنده , , Dmytro Puchkov، نويسنده , , Mark J. Robertson، نويسنده , , Kylie A. MacGregor، نويسنده , , Nikolay Tomilin، نويسنده , , Arndt Pechstein، نويسنده , , Truong Ngoc Chau، نويسنده , , Megan Chircop، نويسنده , , Jennette Sakoff، نويسنده , , Jens-Peter von Kries، نويسنده , , Wolfram Saenger، نويسنده , , Hans-Georg Kr?usslich، نويسنده , , Oleg Shupliakov، نويسنده , , Phillip J. Robinson، نويسنده , , Adam McCluskey، نويسنده , , Volker Haucke، نويسنده ,
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.
