Are zinc-finger domains of protein kinase C dynamic structures that unfold by lipid or redox activation?
Protein kinase C (PKC) is activated by lipid second messengers or redox action, raising the question whether these activation modes involve the same or alternate mechanisms. Here we show that both lipid activators and oxidation target the zinc-finger domains of PKC, suggesting a unifying activation mechanism. We found that lipid agonist-binding or redox action leads to zinc release and disassembly of zinc fingers, thus triggering large-scale unfolding that underlies conversion to the active enzyme. These results suggest that PKC zinc fingers, originally considered purely structural devices, are in fact redox-sensitive flexible hinges, whose conformation is controlled both by redox conditions and lipid agonists.
Immunology Program, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.
Feng
F
Zhao
Marianne
M
Ilbert
Ranjani
R
Varadan
Claudia M
CM
Cremers
Beatrice
B
Hoyos
Rebeca
R
Acin-Perez
Valerie
V
Vinogradov
David
D
Cowburn
Ursula
U
Jakob
Ulrich
U
Hammerling
D000818:Animals; D045304:Cytochromes c / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000235:genetics / Q000378:metabolism; D018095:Germ-Line Mutation / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010703:Phorbol Esters / Q000378:metabolism* / Q000494:pharmacology*; D017510:Protein Folding / Q000187:drug effects; D011493:Protein Kinase C / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
D029968:Escherichia coli Proteins; C492165:HSP33 protein, E coli; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D010703:Phorbol Esters; D011993:Recombinant Fusion Proteins; D045304:Cytochromes c; D011493:Protein Kinase C; D015032:Zinc