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Hierarchically ordered multi-timescale structural dynamics of the intrinsically disordered p53 transactivation domain

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Titel: Hierarchically ordered multi-timescale structural dynamics of the intrinsically disordered p53 transactivation domain
Autoren: Dániel Szöllősi, Supriya Pratihar, Dwaipayan Mukhopadhyay, Ashok Kumar Rout, G. Jithender Reddy, Niklas Ebersberger, Stefan Becker, Gábor Nagy, Sarah Rauscher, Donghan Lee, Reinhard Klement, Christian Griesinger, Helmut Grubmüller
Verlagsinformationen: Cold Spring Harbor Laboratory, 2025.
Publikationsjahr: 2025
Beschreibung: Intrinsically disordered proteins (IDPs) exhibit pronounced structural dynamics, which is crucial for their functional versatility. Yet their dynamics slower than nanoseconds remain largely elusive. We combined high-power relaxation dispersion nuclear magnetic resonance spectroscopy with molecular dynamics simulations to characterize these kinetics and the underlying structural interconversions of a prototypical IDP, the N-terminal transactivation domain of the tumor suppressor p53 (p53-TAD). We find a complex hierarchy of structural dynamics on timescales covering over seven orders of magnitude, ranging from fast nanoseconds backbone re-orientations, via sub-microsecond helix-formation dynamics involving many structural sub-states and transition times, to transient tertiary structure formation slower than 25 microseconds. These rich structural dynamics of p53-TAD, and likely those of other IDPs, parallel the timescale hierarchy of the conformational dynamics of folded proteins. One-Sentence summary A hierarchical energy landscape governs kinetics and structural dynamics of the disordered p53 transactivation domain.
Publikationsart: Article
DOI: 10.1101/2025.08.01.668138
Rights: CC BY NC ND
Dokumentencode: edsair.doi...........59413fbda24e1812b1c8f65e3d8b1d8a
Datenbank: OpenAIRE
Beschreibung
Abstract:Intrinsically disordered proteins (IDPs) exhibit pronounced structural dynamics, which is crucial for their functional versatility. Yet their dynamics slower than nanoseconds remain largely elusive. We combined high-power relaxation dispersion nuclear magnetic resonance spectroscopy with molecular dynamics simulations to characterize these kinetics and the underlying structural interconversions of a prototypical IDP, the N-terminal transactivation domain of the tumor suppressor p53 (p53-TAD). We find a complex hierarchy of structural dynamics on timescales covering over seven orders of magnitude, ranging from fast nanoseconds backbone re-orientations, via sub-microsecond helix-formation dynamics involving many structural sub-states and transition times, to transient tertiary structure formation slower than 25 microseconds. These rich structural dynamics of p53-TAD, and likely those of other IDPs, parallel the timescale hierarchy of the conformational dynamics of folded proteins. One-Sentence summary A hierarchical energy landscape governs kinetics and structural dynamics of the disordered p53 transactivation domain.
DOI:10.1101/2025.08.01.668138