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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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New structural aspects of FKBP38 activation

Mitcheell Maestre-Martínez1, a / Katja Haupt1 / Frank Edlich1, b / Günther Jahreis1 / Franziska Jarczowski1 / Frank Erdmann1 / Gunter Fischer1 / Christian Lücke1

1Max Planck Research Unit for Enzymology of Protein Folding, Weinbergweg 22, D-06120 Halle/Saale, Germany

aPresent address: Max Planck Institute for Biophysical Chemistry, Am Faßberg 11, D-37077 Göttingen, Germany.

bPresent address: National Institute of Neurological Disorders and Stroke, NIH, 35 Convent Drive MSC 3704, Bethesda, MD 20892, USA.

Corresponding author

Citation Information: Biological Chemistry. Volume 391, Issue 10, Pages 1157–1167, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/bc.2010.122, August 2010

Publication History

Received:
2010-03-25
Accepted:
2010-07-05
Published Online:
2010-08-13

Abstract

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 Ca2+-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 Ca2+-dependent interaction of the CaM-binding motif at the C-terminal end of FKBP38 with the C-terminal CaM lobe and (ii) a Ca2+-independent interaction between the N-terminal CaM lobe and the N-terminal region of the catalytic FKBP38 domain.

Keywords: Bcl-2; calmodulin; chemical shift perturbation mapping; FK506 binding protein; PPIase; protein-protein interactions

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[1]
Martin W. Berchtold and Antonio Villalobo
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2014, Volume 1843, Number 2, Page 398
[2]
Frank Edlich and Christian Lücke
Current Opinion in Pharmacology, 2011, Volume 11, Number 4, Page 348

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