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 Ca 2 sensor calmodulin (CaM). Here we demonstrate for the first time that the formation of a complex between FKBP38 and CaM-Ca 2 involves two separate interaction sites, thus revealing a novel scenario of target protein regulation by CaM-Ca 2 . The C-terminal FKBP38 residues Ser 290 -Asn 313 bind to the target protein-binding cleft of the Ca 2 -coordinated C-terminal CaM domain, thereby enabling the N-terminal CaM domain to interact with the catalytic domain of FKBP38 in a Ca 2 -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.