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Electrostatic contribution of phosphorylation to the stability of the CREB–CBP activator–coactivator complex

Nature Structural Biology volume 6, pages 613–614 (1999)Cite this article

The cyclic AMP- and calcium-regulated transcriptional activator CREB (cAMP response element binding protein) regulates transcription in part by binding the coactivator CBP (CREB-binding protein)1,2. CBP then contributes to transcriptional activation through interactions with RNA polymerase II and/or through histone acetyltransferase activity1,2,3,4. The CREB–CBP interaction is functionally localized to the KID domain of CREB and the KIX domain of CBP5, with phosphorylation of KID at Ser 133 facilitating the interaction between CREB and CBP5,6,7.

The electrostatic contribution of the Ser 133 phosphate group to the stability of the complex can be determined directly from the difference in pKa values of the phosphate group in free KID and in the KID–KIX complex11,17. The pKa will be lowered in the bound state relative to the unbound state if the negatively charged phosphate group contributes favorably to stability. Conversely, if the charged group does not contribute to stability, or is destabilizing, relative to the protonated form, then the pKa will be unperturbed or elevated, respectively, in the complex.

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Figure 1
Figure 2: a, The KID—KIX complex is unstable below pH 4.5, as indicated by a loss of helicity monitored by CD spectroscopy at 222 nm, precluding study of the complex at low pH. Since KIX unfolds at low pH, the instability of the KID—KIX complex is driven at least in part by the instability of KIX at low pH.

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Acknowledgements

We thank C. Rithner, L. Stargell and R. Woody for helpful discussions, I. Radhakrishnan and P. Wright for the KID—KIX coordinates, and R. Goodman for the pRC/RSV—CBP plasmid. The work was supported by the American Chemical Society Petroleum Research Fund and the McNair Scholars Program.

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  1. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, 80523-1870, Colorado, USA

    Santano P. Mestas & Kevin J. Lumb

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Correspondence to Kevin J. Lumb.

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Mestas, S., Lumb, K. Electrostatic contribution of phosphorylation to the stability of the CREB–CBP activator–coactivator complex. Nat Struct Mol Biol 6, 613–614 (1999). https://doi.org/10.1038/10655

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