Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition.
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Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. / von Kleist, Lisa; Stahlschmidt, Wiebke; Bulut, Haydar; Brune, Kira; Puchkov, Dmytro; Robertson, Mark J; MacGregor, Kylie A; Tomilin, Nikolay; Tomlin, Nikolay; Pechstein, Arndt; Chau, Ngoc; Chircop, Megan; Sakoff, Jennette; Kries, von; Peter, Jens; Saenger, Wolfram; Kräusslich, Hans-Georg; Shupliakov, Oleg; Robinson, Phillip J; McCluskey, Adam; Haucke, Volker.
in: CELL, Jahrgang 146, Nr. 3, 3, 2011, S. 471-484.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition.
AU - von Kleist, Lisa
AU - Stahlschmidt, Wiebke
AU - Bulut, Haydar
AU - Brune, Kira
AU - Puchkov, Dmytro
AU - Robertson, Mark J
AU - MacGregor, Kylie A
AU - Tomilin, Nikolay
AU - Tomlin, Nikolay
AU - Pechstein, Arndt
AU - Chau, Ngoc
AU - Chircop, Megan
AU - Sakoff, Jennette
AU - Kries, von
AU - Peter, Jens
AU - Saenger, Wolfram
AU - Kräusslich, Hans-Georg
AU - Shupliakov, Oleg
AU - Robinson, Phillip J
AU - McCluskey, Adam
AU - Haucke, Volker
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Endocytosis
KW - Protein Structure, Tertiary
KW - Signal Transduction
KW - Crystallography, X-Ray
KW - Adaptor Protein Complex 2/metabolism
KW - Clathrin/chemistry/metabolism
KW - Coated Pits, Cell-Membrane/drug effects/metabolism
KW - Cytological Techniques/methods
KW - Dynamins/metabolism
KW - Small Molecule Libraries
KW - Synapses/metabolism/ultrastructure
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Mice
KW - Endocytosis
KW - Protein Structure, Tertiary
KW - Signal Transduction
KW - Crystallography, X-Ray
KW - Adaptor Protein Complex 2/metabolism
KW - Clathrin/chemistry/metabolism
KW - Coated Pits, Cell-Membrane/drug effects/metabolism
KW - Cytological Techniques/methods
KW - Dynamins/metabolism
KW - Small Molecule Libraries
KW - Synapses/metabolism/ultrastructure
M3 - SCORING: Journal article
VL - 146
SP - 471
EP - 484
JO - CELL
JF - CELL
SN - 0092-8674
IS - 3
M1 - 3
ER -