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Sci Adv. 2018 Oct 24;4(10):eaau4130. doi: 10.1126/sciadv.aau4130. eCollection 2018 Oct.

Structure and dynamics conspire in the evolution of affinity between intrinsically disordered proteins.

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Department of Medical Biochemistry and Microbiology, Uppsala University, BMC Box 582, SE-75123 Uppsala, Sweden.
Department of Biochemistry and Molecular Genetics, University of Colorado at Denver, 12801 East 17th Avenue, Aurora, CO 80045, USA.
Protein Physiology Lab, FCEyN-Universidad de Buenos Aires, IQUIBICEN/CONICET, Intendente Güiraldes 2160, Ciudad Universitaria, C1428EGA Buenos Aires, Argentina.
Department of Pharmaceutical Biosciences, Uppsala University, BMC Box 591, SE-75124 Uppsala, Sweden.
Department of Biochemistry and Biophysics, Stockholm University, SE-10691 Stockholm, Sweden.
Laboratory of Physical Chemistry, ETH Zürich, ETH-Hönggerberg, Zürich, Switzerland.
Institute of Biophysical Chemistry, Center for Biomolecular Magnetic Resonance, Goethe University, 60438 Frankfurt am Main, Germany.
Graduate School of Science, Tokyo Metropolitan University, Tokyo 192-0397, Japan.


In every established species, protein-protein interactions have evolved such that they are fit for purpose. However, the molecular details of the evolution of new protein-protein interactions are poorly understood. We have used nuclear magnetic resonance spectroscopy to investigate the changes in structure and dynamics during the evolution of a protein-protein interaction involving the intrinsically disordered CREBBP (CREB-binding protein) interaction domain (CID) and nuclear coactivator binding domain (NCBD) from the transcriptional coregulators NCOA (nuclear receptor coactivator) and CREBBP/p300, respectively. The most ancient low-affinity "Cambrian-like" [540 to 600 million years (Ma) ago] CID/NCBD complex contained less secondary structure and was more dynamic than the complexes from an evolutionarily younger "Ordovician-Silurian" fish ancestor (ca. 440 Ma ago) and extant human. The most ancient Cambrian-like CID/NCBD complex lacked one helix and several interdomain interactions, resulting in a larger solvent-accessible surface area. Furthermore, the most ancient complex had a high degree of millisecond-to-microsecond dynamics distributed along the entire sequences of both CID and NCBD. These motions were reduced in the Ordovician-Silurian CID/NCBD complex and further redistributed in the extant human CID/NCBD complex. Isothermal calorimetry experiments show that complex formation is enthalpically favorable and that affinity is modulated by a largely unfavorable entropic contribution to binding. Our data demonstrate how changes in structure and motion conspire to shape affinity during the evolution of a protein-protein complex and provide direct evidence for the role of structural, dynamic, and frustrational plasticity in the evolution of interactions between intrinsically disordered proteins.

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