Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 31, Pages 9614-9619Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1512799112
Keywords
intrinsically disordered protein; coupled folding and binding; NMR relaxation; transcriptional coactivator CBP; transcriptional activator c-Myb
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Funding
- National Institutes of Health [CA096865]
- Skaggs Institute for Chemical Biology
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Kurata Memorial Hitachi Science and Technology Foundation
- Sumitomo Foundation
- Asahi Glass Foundation
- Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency
- Grants-in-Aid for Scientific Research [15K07023, 15H01311] Funding Source: KAKEN
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Intrinsically disordered proteins (IDPs) frequently function in protein interaction networks that regulate crucial cellular signaling pathways. Many IDPs undergo transitions from disordered conformational ensembles to folded structures upon binding to their cellular targets. Several possible binding mechanisms for coupled folding and binding have been identified: folding of the IDP after association with the target ( induced fit), or binding of a prefolded state in the conformational ensemble of the IDP to the target protein ( conformational selection), or some combination of these two extremes. The interaction of the intrinsically disordered phosphorylated kinase-inducible domain (pKID) of the cAMP-response element binding (CREB) protein with the KIX domain of a general transcriptional coactivator CREB-binding protein (CBP) provides an example of the induced-fit mechanism. Here we show by NMR relaxation dispersion experiments that a different intrinsically disordered ligand, the transactivation domain of the transcription factor c-Myb, interacts with KIX at the same site as pKID but via a different binding mechanism that involves elements of conformational selection and induced fit. In contrast to pKID, the c-Myb activation domain has a strong propensity for spontaneous helix formation in its N-terminal region, which binds to KIX in a predominantly folded conformation. The C-terminal region of c-Myb exhibits a much smaller helical propensity and likely folds via an induced-fit process after binding to KIX. We propose that the intrinsic secondary structure propensities of pKID and c-Myb determine their binding mechanisms, consistent with their functions as inducible and constitutive transcriptional activators.
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