Defining Conformational Ensembles of Intrinsically Disordered and Partially Folded Proteins Directly from Chemical Shifts

Jensen, Malene Ringkjøbing; Salmon, Loïc; Nodet, Gabrielle; Blackledge, Martin

doi:10.1021/ja909973n

Cited by 167 publications

(176 citation statements)

References 39 publications

(90 reference statements)

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“…Another approach for creating an ensemble that agrees with experimental measurements involves generating structures using a statistical coil-like model (Flexible-Meccano), a subset of which are selected for the agreement between their backbone dihedral angles and NMR chemical shifts. The process is then iterated until no further improvement in the agreement between chemical shifts and backbone dihedral angles can be obtained [90]. These models and their associated experimental data can be deposited in an openly accessible database termed pE-DB [91].…”

Section: Computational Methods For Describing Idp Ensemblesmentioning

confidence: 99%

Intrinsically Disordered Proteins: Where Computation Meets Experiment

2014

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Proteins are heteropolymers that play important roles in virtually every biological reaction. While many proteins have well-defined three-dimensional structures that are inextricably coupled to their function, intrinsically disordered proteins (IDPs) do not have a well-defined structure, and it is this lack of structure that facilitates their function. As many IDPs are involved in essential cellular processes, various diseases have been linked to their malfunction, thereby making them important drug targets. In this review we discuss methods for studying IDPs and provide examples of how computational methods can improve our understanding of IDPs. We focus on two intensely studied IDPs that have been implicated in very different pathologic pathways. The first, p53, has been linked to over 50% of human cancers, and the second, Amyloid-β (Aβ), forms neurotoxic aggregates in the brains of patients with Alzheimer's disease. We use these representative proteins to illustrate some of the challenges associated with studying IDPs and demonstrate how computational tools can be fruitfully applied to arrive at a more comprehensive understanding of these fascinating heteropolymers. OPEN ACCESSPolymers 2014, 6 2685

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Section: Computational Methods For Describing Idp Ensemblesmentioning

confidence: 99%

Intrinsically Disordered Proteins: Where Computation Meets Experiment

2014

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“…43 To date, the approach has been applied to experimental measurements that depend essentially on local structural behavior, such as residual dipolar couplings (RDCs) and chemical shifts. 44 Here we have adapted the approach to incorporate the interpretation of PREs. In order to allow for flexibility of the spin label with respect to the backbone conformation, explicit rotameric libraries that have been parametrized against experimental electron spin resonance (ESR) measurements and MD simulations 45 are used to map the allowed position of the electron spin.…”

Section: Introductionmentioning

confidence: 99%

NMR Characterization of Long-Range Order in Intrinsically Disordered Proteins

et al. 2010

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Intrinsically disordered proteins (IDPs) are predicted to represent a significant fraction of the human genome, and the development of meaningful molecular descriptions of these proteins remains a key challenge for contemporary structural biology. In order to describe the conformational behavior of IDPs, a molecular representation of the disordered state based on diverse sources of structural data that often exhibit complex and very different averaging behavior is required. In this study, we propose a combination of paramagnetic relaxation enhancements (PREs) and residual dipolar couplings (RDCs) to define both long-range and local structural features of IDPs in solution. We demonstrate that ASTEROIDS, an ensemble selection algorithm, faithfully reproduces intramolecular contacts, even in the presence of highly diffuse, ill-defined target interactions. We also show that explicit modeling of spin-label mobility significantly improves the reproduction of experimental PRE data, even in the case of highly disordered proteins. Prediction of the effects of transient long-range contacts on RDC profiles reveals that weak intramolecular interactions can induce a severe distortion of the profiles that compromises the description of local conformational sampling if it is not correctly taken into account. We have developed a solution to this problem that involves efficiently combining RDC and PRE data to simultaneously determine long-range and local structure in highly flexible proteins. This combined analysis is shown to be essential for the accurate interpretation of experimental data from R-synuclein, an important IDP involved in human neurodegenerative disease, confirming the presence of long-range order between distant regions in the protein.

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“…The structure of a disordered peptide chain is thus far from random, and we will use the term statistical coil instead of ''random coil'' throughout the remainder of this text. Subsequent studies have shown that some IDPs required a higher proportion of helical-or PPII-like conformations to fit the experimental data, 17,18 which underscores that the free energy landscape for residual structure in IDPs is best evaluated on a case-to-case basis and with residue resolution.…”

Section: Introductionmentioning

confidence: 99%

Temperature‐dependent structural changes in intrinsically disordered proteins: Formation of α‒helices or loss of polyproline II?

Kjærgaard¹,

Nørholm²,

et al. 2010

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Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number of circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation of transient a-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural change is common among IDPs and is accompanied by a contraction of the conformational ensemble. This phenomenon was explored at residue resolution by multidimensional NMR spectroscopy. Intrinsic chemical shift referencing allowed us to identify regions of transiently formed helices and their temperature-dependent changes in helicity. All helical regions were found to lose rather than gain helical structures with increasing temperature, and accordingly these were not responsible for the change in the CD spectra. In contrast, the nonhelical regions exhibited a general temperature-dependent structural change that was independent of long-range interactions. The temperature-dependent CD spectroscopic signature of IDPs that has been amply documented can be rationalized to represent redistribution of the statistical coil involving a general loss of PPII conformations.Keywords: intrinsically disordered protein (IDP); transient secondary structure; temperature dependence; polyproline II; circular dichroism (CD); nuclear magnetic resonance spectroscopy (NMR); sodium-proton (Na1/H1) exchanger 1 (NHE1); S-phase delayed 1 (Spd1); activator for thyroid hormone and retinoid receptors (ACTR) Abbreviations: ACTR, activator for thyroid hormone and retinoid receptors; CBP, CREB-binding protein; CD, circular dichroism; IDP, intrinsically disordered protein; NCBD, nuclear coactivator binding domain; NHE1cdt, sodium-proton (Na þ /H þ ) exchanger 1 C-terminal distal tail; NMR, nuclear magnetic resonance; PPII, polyproline II; RDC, residual dipolar coupling; SAXS, small-angle X-ray scattering; Spd1, S-phase delayed 1.

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Defining Conformational Ensembles of Intrinsically Disordered and Partially Folded Proteins Directly from Chemical Shifts

Cited by 167 publications

References 39 publications

Intrinsically Disordered Proteins: Where Computation Meets Experiment

Intrinsically Disordered Proteins: Where Computation Meets Experiment

NMR Characterization of Long-Range Order in Intrinsically Disordered Proteins

Temperature‐dependent structural changes in intrinsically disordered proteins: Formation of α‒helices or loss of polyproline II?

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