ORCID Profile
0000-0001-8623-7743
Current Organisation
京都大学 / Kyoto University
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Publisher: Elsevier BV
Date: 02-2008
Publisher: Proceedings of the National Academy of Sciences
Date: 20-07-2015
Abstract: Intrinsically disordered proteins play a central role in cellular signaling and regulatory networks. Many regulatory proteins contain disordered recognition motifs that fold upon binding to their cellular targets, by mechanisms that are poorly understood. Here we show that the disordered transactivation domain of the transcription factor c-Myb binds to the KIX domain of the transcriptional coactivator cAMP-response element binding (CREB-binding) protein (CBP) by a mechanism that involves elements of conformational selection and induced fit. In contrast, the phosphorylated kinase-inducible activation domain of CREB binds to the same site on KIX by an induced-fit mechanism. The intrinsic secondary structure propensities of these two disordered proteins determine their binding mechanisms, consistent with their functions as inducible and constitutive transcriptional activators.
Publisher: Springer Science and Business Media LLC
Date: 23-05-2007
DOI: 10.1038/NATURE05858
Abstract: Protein folding and binding are analogous processes, in which the protein 'searches' for favourable intramolecular or intermolecular interactions on a funnelled energy landscape. Many eukaryotic proteins are disordered under physiological conditions, and fold into ordered structures only on binding to their cellular targets. The mechanism by which folding is coupled to binding is poorly understood, but it has been hypothesized on theoretical grounds that the binding kinetics may be enhanced by a 'fly-casting' effect, where the disordered protein binds weakly and non-specifically to its target and folds as it approaches the cognate binding site. Here we show, using NMR titrations and (15)N relaxation dispersion, that the phosphorylated kinase inducible activation domain (pKID) of the transcription factor CREB forms an ensemble of transient encounter complexes on binding to the KIX domain of the CREB binding protein. The encounter complexes are stabilized primarily by non-specific hydrophobic contacts, and evolve by way of an intermediate to the fully bound state without dissociation from KIX. The carboxy-terminal helix of pKID is only partially folded in the intermediate, and becomes stabilized by intermolecular interactions formed in the final bound state. Future applications of our method will provide new understanding of the molecular mechanisms by which intrinsically disordered proteins perform their erse biological functions.
Publisher: Springer Science and Business Media LLC
Date: 17-12-2019
DOI: 10.1038/S41598-019-55806-3
Abstract: ShK is a 35-residue disulfide-linked polypeptide produced by the sea anemone Stichodactyla helianthus , which blocks the potassium channels Kv1.1 and Kv1.3 with pM affinity. An analogue of ShK has been developed that blocks Kv1.3 100 times more potently than Kv1.1, and has completed Phase 1b clinical trials for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. Previous studies have indicated that ShK undergoes a conformational exchange that is critical to its function, but this has proved difficult to characterise. Here, we have used high hydrostatic pressure as a tool to increase the population of the alternative state, which is likely to resemble the active form that binds to the Kv1.3 channel. By following changes in chemical shift with pressure, we have derived the chemical shift values of the low- and high-pressure states, and thus characterised the locations of structural changes. The main difference is in the conformation of the Cys17-Cys32 disulfide, which is likely to affect the positions of the critical Lys22-Tyr23 pair by twisting the 21–24 helix and increasing the solvent exposure of the Lys22 sidechain, as indicated by molecular dynamics simulations.
Location: Japan
No related grants have been discovered for Kenji Sugase.