title: A novel calmodulin-Ca2+ target recognition activates the Bcl-2 regulator FKBP38.
abstract: The FK506-binding protein 38 (FKBP38) affects neuronal apoptosis control by suppressing the anti-apoptotic function of Bcl-2. The direct interaction between FKBP38 and Bcl-2, however, requires a prior activation of FKBP38 by the Ca2+ sensor calmodulin (CaM). Here we demonstrate for the first time that the formation of a complex between FKBP38 and CaM-Ca2+ involves two separate interaction sites, thus revealing a novel scenario of target protein regulation by CaM-Ca2+. The C-terminal FKBP38 residues Ser290-Asn313 bind to the target protein-binding cleft of the Ca2+-coordinated C-terminal CaM domain, thereby enabling the N-terminal CaM domain to interact with the catalytic domain of FKBP38 in a Ca2+-independent manner. Only the latter interaction between the catalytic FKBP38 domain and the N-terminal CaM domain activates FKBP38 and, as a consequence, also regulates Bcl-2.
authors.affiliation: Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany. edlich@enzyme-halle.mpg.de
authors.forename: Frank
authors.initials: F
authors.lastname: Edlich
authors.forename: Mitcheell
authors.initials: M
authors.lastname: Maestre-Martínez
authors.forename: Franziska
authors.initials: F
authors.lastname: Jarczowski
authors.forename: Matthias
authors.initials: M
authors.lastname: Weiwad
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Moutty
authors.forename: Miroslav
authors.initials: M
authors.lastname: Malesević
authors.forename: Günther
authors.initials: G
authors.lastname: Jahreis
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Christian
authors.initials: C
authors.lastname: Lücke
mesh_terms: D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002474:Cell-Free System / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D002147:Calmodulin; C471205:FKBP8 protein, human; D046912:Multiprotein Complexes; D019253:Proto-Oncogene Proteins c-bcl-2; D022021:Tacrolimus Binding Proteins; D002118:Calcium