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Backbone Dynamics of a Symmetric Calmodulin Dimer in Complex with the Calmodulin-Binding Domain of the Basic-Helix-Loop-Helix Transcription Factor SEF2-1/E2-2: A Highly Dynamic Complex

Göran Larsson ^*, Jürgen Schleucher ^*, Jacqueline Onions , Stefan Hermann , Thomas Grundström  and Sybren S. Wijmenga ^*

^* Department of Medical Biochemistry and Biophysics, and Department of Molecular Biology, University of Umeå, S-901 87 Umeå, Sweden

Correspondence: Address reprint requests to Sybren Wijmenga, Dept. of Physical Chemistry-Laboratory of Biophysical Chemistry, University of Nijmegen, Toernooiveld 1, 6525 ED, Nijmegen, The Netherlands. Tel.: 31-24-3652678/3384; Fax: 31-24-3652112; E-mail: sybren.wijmenga{at}sci.kun.nl.

Calmodulin (CaM) interacts specifically as a dimer with some dimeric basic-Helix-Loop-Helix (bHLH) transcription factors via a novel high affinity binding mode. Here we report a study of the backbone dynamics by ¹⁵N-spin relaxation on the CaM dimer in complex with a dimeric peptide that mimics the CaM binding region of the bHLH transcription factor SEF2-1. The relaxation data were measured at multiple magnetic fields, and analyzed in a model-free manner using in-house written software designed to detect nanosecond internal motion. Besides picosecond motions, all residues also experience internal motion with an effective correlation time of 2.5 ns with squared order parameter (S²) of 0.75. Hydrodynamic calculations suggest that this can be attributed to motions of the N- and C-terminal domains of the CaM dimer in the complex. Moreover, residues with significant exchange broadening are found. They are clustered in the CaM:SEF2-1mp binding interface, the CaM:CaM dimer interface, and in the flexible helix connecting the CaM N- and C-terminal domains, and have similar exchange times (50 µs), suggesting a cooperative mechanism probably caused by protein:protein interactions. The dynamic features presented here support the conclusion that the conformationally heterogeneous bHLH mimicking peptide trapped inside the CaM dimer exchanges between different binding sites on both nanosecond and microsecond timescales. Nature has thus found a way to specifically recognize a relatively ill-fitting target. This novel mode of target-specific binding, which neither belongs to lock-and-key nor induced-fit binding, is characterized by dimerization and continuous exchange between multiple flexible binding alternatives.

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