Bcl-2 regulator FKBP38 is activated by Ca2+/calmodulin.
FKBP-type peptidyl prolyl cis/trans isomerases (PPIases) are folding helper enzymes involved in the control of functional regrowth of damaged sciatic, cortical cholinergic, dopaminergic and 5-HT neurones. Here, we show that the constitutively inactive human FK506-binding protein 38 (FKBP38) is capable of responding directly to intracellular Ca2+ rise through formation of a heterodimeric Ca2+/calmodulin/FKBP38 complex. Only complex formation creates an enzymatically active FKBP, displaying affinity for Bcl-2 mediated through the PPIase site. Association between Bcl-2 and the active site of Ca2+/calmodulin/FKBP38 regulates Bcl-2 function and thereby participates in the promotion of apoptosis in neuronal tissues. FKBP38 proapoptotic function mediated by this interaction is abolished by either potent inhibitors of the PPIase activity of the Ca2+/calmodulin/FKBP38 complex or RNA interference-mediated depletion of FKBP38, promoting neuronal cell survival.
Max-Planck Research Unit for Enzymology of Protein Folding, Halle/Saale, Germany.
Frank
F
Edlich
Matthias
M
Weiwad
Frank
F
Erdmann
Jörg
J
Fanghänel
Franziska
F
Jarczowski
Jens-Ulrich
JU
Rahfeld
Gunter
G
Fischer
D017209:Apoptosis / Q000502:physiology; D001665:Binding Sites; D002118:Calcium / Q000502:physiology*; D002147:Calmodulin / Q000737:chemistry / Q000502:physiology*; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D006801:Humans; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
D002147:Calmodulin; C471205:FKBP8 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D002118:Calcium