The Bcl-2 regulator FKBP38-calmodulin-Ca2+ is inhibited by Hsp90.
FKBP38 is a negative effector of the anti-apoptotic Bcl-2 protein in neuroblastoma cells. The interaction with Bcl-2 and the enzyme activity of FKBP38 depend on prior binding of calmodulin-Ca(2+) (CaM-Ca(2+)) at high Ca(2+) concentrations. The FKBP38 protein structure contains three tetratricopeptide repeat (TPR) motifs corresponding to the Hsp90 interaction sites of other immunophilins. In this study we show that the TPR domain of FKBP38 interacts with the C-terminal domain of Hsp90, but only if the FKBP38-CaM-Ca(2+) complex is preformed. Hence, FKBP38 is the first example of a TPR-containing immunophilin that interacts cofactor-dependently with Hsp90. In the ternary Hsp90-FKBP38-CaM-Ca(2+) complex the active site of FKBP38 is blocked, thus preventing interactions with Bcl-2. The dual control of the active site cleft of FKBP38 by CaM-Ca(2+) and Hsp90 highlights the importance of the enzyme activity of the FKBP38-CaM-Ca(2+) complex in the regulation of programmed cell death.
Edlich
Frank
F
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany.
Erdmann
Frank
F
Jarczowski
Franziska
F
Moutty
Marie-Christine
MC
Weiwad
Matthias
M
Fischer
Gunter
G
D020816:Amino Acid Motifs; D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry* / Q000378:metabolism; D002474:Cell-Free System / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D020836:Protein Structure, Quaternary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000378:metabolism
D002147:Calmodulin; C471205:FKBP8 protein, human; D018841:HSP90 Heat-Shock Proteins; D046912:Multiprotein Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D022021:Tacrolimus Binding Proteins; D002118:Calcium