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

Cell. 2011 Aug 5;146(3):471-84. doi: 10.1016/j.cell.2011.06.025.

Lisa von Kleist ¹, Wiebke Stahlschmidt, Haydar Bulut, Kira Gromova, Dmytro Puchkov, Mark J Robertson, Kylie A MacGregor, Nikolay Tomilin, Arndt Pechstein, Ngoc Chau, Megan Chircop, Jennette Sakoff, Jens Peter von Kries, Wolfram Saenger, Hans-Georg Kräusslich, Oleg Shupliakov, Phillip J Robinson, Adam McCluskey, Volker Haucke

Affiliations

Affiliation

1 Institute of Chemistry and Biochemistry & Neurocure Cluster of Excellence, Freie Universität Berlin, 14195 Berlin, Germany.

PMID: 21816279 DOI: 10.1016/j.cell.2011.06.025

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-102068

Clathrin-IN-1

Clathrin-mediated Endocytosis Inhibitor

HIV

Infection

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