New structural aspects of FKBP38 activation.
The human FK506-binding protein 38 (FKBP38) regulates Bcl-2 in neuronal apoptosis. To control Bcl-2 activity, FKBP38 requires a prior interaction with the Ca(2+)-sensor calmodulin (CaM). The resulting FKBP38/CaM complex is unique within the FKBP family. Here, we present novel insights into the structural arrangement of this complex. Chemical shift perturbation analyses of the individual protein domains revealed two separate interaction sites between FKBP38 and CaM. On the one hand, residues Glu303, Tyr307 and Leu311, belonging to the predicted CaM-binding site at the C-terminal end of FKBP38, become embedded in the hydrophobic target protein-binding cleft of the C-terminal CaM lobe. On the other hand, in a second binding interaction, the N-terminal end of the catalytic FKBP38 domain shows surface contacts to the AB and CD loops of CaM as well as the adjacent helices. Furthermore, a Glu-rich region at the non-structured FKBP38 N-terminus features additional contacts to CaM helix A. In combination with previous results, we thus conclude that the FKBP38/CaM complex is constituted by (i) a Ca(2+)-dependent interaction of the CaM-binding motif at the C-terminal end of FKBP38 with the C-terminal CaM lobe and (ii) a Ca(2+)-independent interaction between the N-terminal CaM lobe and the N-terminal region of the catalytic FKBP38 domain.
Maestre-Martínez
Mitcheell
M
Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany.
Haupt
Katja
K
Edlich
Frank
F
Jahreis
Günther
G
Jarczowski
Franziska
F
Erdmann
Frank
F
Fischer
Gunter
G
Lücke
Christian
C
D000595:Amino Acid Sequence; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000737:chemistry / Q000378:metabolism; D020134:Catalytic Domain; D002460:Cell Line; D004789:Enzyme Activation; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D022021:Tacrolimus Binding Proteins / Q000737:chemistry* / Q000378:metabolism*
D001059:Apoproteins; D002147:Calmodulin; C471205:FKBP8 protein, human; D022021:Tacrolimus Binding Proteins; D002118:Calcium