Biomolecular mimicry in the actin cytoskeleton: mechanisms underlying the cytotoxicity of kabiramide C and related macrolides.
This study characterizes the interactions between kabiramide C (KabC) and related macrolides and actin and establishes the mechanisms that underlie their inhibition of actin filament dynamics and cytotoxicity. The G-actin-KabC complex is formed through a two-step binding reaction and is extremely stable and long-lived. Competition-binding studies show that KabC binds to the same site on G-actin as Gelsolin domain 1 and CapG. KabC also binds to protomers within F-actin and results in the severing and capping of the (+) end; these studies suggest that free KabC and related macrolides act as biomimetics of Gelsolin. The G-actin-KabC complex binds to the (+) end of a growing filament, where it functions as a novel, unregulated, (+)-end capper and is largely responsible for the inhibition of motility and cytokinesis in approximately 10 -100 nM KabC-treated cells. KabC and related macrolides are useful probes to study the regulation of the actin filament (+) end and may lead to new therapies to treat diseases of the actin cytoskeleton.
Tanaka
Junichi
J
Department of Physiology, University of Wisconsin, 1300 University Avenue, Madison, WI 53706, USA.
Yan
Yuling
Y
Choi
Jeongeun
J
Bai
Jihong
J
Klenchin
Vadim A
VA
Rayment
Ivan
I
Marriott
Gerard
G
D015081:2-Naphthylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D000199:Actins / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D018260:Gelsolin / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D018942:Macrolides / Q000737:chemistry / Q000633:toxicity*; D008386:Marine Biology; D051379:Mice; D008840:Microfilament Proteins / Q000737:chemistry / Q000378:metabolism; D018716:Molecular Mimicry; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000633:toxicity*; D010641:Phenotype; D011161:Porifera / Q000737:chemistry; D011485:Protein Binding; D051381:Rats
D000199:Actins; D018260:Gelsolin; D018942:Macrolides; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D010080:Oxazoles; C483826:Capg protein, mouse; C082008:jaspisamide A; C038517:prodan; D015081:2-Naphthylamine