Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition | Zendy

Lisa von Kleist | Zendy; Wiebke Stahlschmidt | Zendy; Haydar Bulut | Zendy; Kira V. Gromova | Zendy; Dmytro Puchkov | Zendy; Mark J. Robertson | Zendy; Kylie A. MacGregor | Zendy; N.V. Tomilin | Zendy; Arndt Pechstein | Zendy; Ngoc Chau | Zendy; Megan Chircop | Zendy; Jennette A. Sakoff | Zendy; Jens Peter von Kries | Zendy; Wolfram Saenger | Zendy; HansGeorg Kräusslich | Zendy; Oleg Shupliakov | Zendy; Phillip J. Robinson | Zendy; Adam McCluskey | Zendy; Volker Haucke | Zendy

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Role of the Clathrin Terminal Domain in Regulating Coated Pit Dynamics Revealed by Small Molecule Inhibition

Author(s) -

Lisa von Kleist,

Wiebke Stahlschmidt,

Haydar Bulut,

Kira V. Gromova,

Dmytro Puchkov,

Mark J. Robertson,

Kylie A. MacGregor,

N.V. Tomilin,

Arndt Pechstein,

Ngoc Chau,

Megan Chircop,

Jennette A. Sakoff,

Jens Peter von Kries,

Wolfram Saenger,

HansGeorg Kräusslich,

Oleg Shupliakov,

Phillip J. Robinson,

Adam McCluskey,

Volker Haucke

Publication year - 2011

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2011.06.025

Subject(s) - clathrin , endocytic cycle , endocytosis , biology , microbiology and biotechnology , receptor mediated endocytosis , dynamin , internalization , amphiphysin , bulk endocytosis , receptor , biochemistry

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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