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• W2952669678 abstract "NMR’s unique capacity to provide structural and dynamic information at atomic resolution is key to study one of the current frontiers of structural biology: the intrinsically disordered regions (IDRs) that are present in two-thirds of eukaryotic proteins (1Wright P.E. Dyson H.J. Intrinsically disordered proteins in cellular signalling and regulation.Nat. Rev. Mol. Cell Biol. 2015; 16: 18-29Crossref PubMed Scopus (1346) Google Scholar, 2Gsponer J. Futschik M.E. Babu M.M. et al.Tight regulation of unstructured proteins: from transcript synthesis to protein degradation.Science. 2008; 322: 1365-1368Crossref PubMed Scopus (356) Google Scholar). These flexible regions encode a wealth of information essential to understand regulatory systems, sensing the complex cellular environment and acting as programmable platforms modified by posttranslational modifications or alternative splicing (3Chin A.F. Toptygin D. Hilser V.J. et al.Phosphorylation increases persistence length and end-to-end distance of a segment of tau protein.Biophys. J. 2016; 110: 362-371Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 4Zhou J. Zhao S. Dunker A.K. Intrinsically disordered proteins link alternative splicing and post-translational modifications to complex cell signaling and regulation.J. Mol. Biol. 2018; 430: 2342-2359Crossref PubMed Scopus (48) Google Scholar). The exquisite sensitivity of IDRs to their environment makes it essential to study them under physiological conditions. The noninvasive character of NMR is compatible with these requirements, enabling the study of IDRs even in the cytoplasm of living cells. The main limitation of NMR is a low signal/noise ratio, alleviated by time averaging of repeated experiments. Thus, optimizing data acquisition has a direct impact on the capacity to address physiologically relevant questions. NMR spectra are acquired by measuring the time evolution of a set of spins taken out of equilibrium through a sequence of radiofrequency pulses. The observed signal decays with time, but, even when no more signal can be measured, the system may not have fully relaxed; thus, long waiting times are necessary before the experiment can be repeated. The relaxation rates depend on the modulation of the spin environment by molecular motions. Rigid globular proteins have characteristically slow reorientations, but relaxation in the flexible IDRs depends on much faster local motions. This results in sharper NMR lines but also on longer relaxation times for IDRs, as compared to globular proteins. Two additional limitations related to the intrinsic flexibility of IDRs are the narrow spectral dispersion of their 1H NMR signals and the potential broadening of the exposed amide proton signals by exchange with the solvent. Improvements in instrumental sensitivity have made direct detection of heteronuclear 13C spectra, in particular, the two-dimensional CON experiment, a widely used choice for the study of IDRs (5Bermel W. Bertini I. Pierattelli R. et al.Protonless NMR experiments for sequence-specific assignment of backbone nuclei in unfolded proteins.J. Am. Chem. Soc. 2006; 128: 3918-3919Crossref PubMed Scopus (154) Google Scholar). The CON experiment relies on direct detection of 13C and exploits the wide dispersion of 13CO and 15N signals in peptide bonds. CON has advantages over proton-detected heteronuclear single-quantum coherence, also providing a residue-specific fingerprint: in addition to the larger spectral dispersion, CON are not affected by solvent exchange and allow observation of proline signals, which are highly abundant in IDRs. However, slow relaxation limits the speed at which the experiments can be repeated to increase sensitivity, and a substantial amount of valuable spectrometer time is lost just waiting for the spins to return to their equilibrium state. In this issue, Schiavina et al. (6Schiavina H. Murrali M.G. Felli I.C. et al.Taking simultaneous snapshots of intrinsically disordered proteins in action.Biophys. J. 2019; 117: 46-55Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) show that entire NMR experiment(s) can be embedded in the relaxation time between consecutive scans of the CON experiment, like Matryoshka Russian dolls (Fig. 1). This approach efficiently fills in the “empty” time that would otherwise be lost just waiting for the system to relax before the experiment can be repeated. The new series of experiments exploit the use of multiple receivers of the newest NMR spectrometers (7Kupče E. Freeman R. John B.K. Parallel acquisition of two-dimensional NMR spectra of several nuclear species.J. Am. Chem. Soc. 2006; 128: 9606-9607Crossref PubMed Scopus (86) Google Scholar). Whereas the method follows earlier ideas about activating unexploited magnetization (UTOPIA) (8Viegas A. Viennet T. Etzkorn M. et al.UTOPIA NMR: activating unexploited magnetization using interleaved low-gamma detection.J. Biomol. NMR. 2016; 64: 9-15Crossref PubMed Scopus (15) Google Scholar) and combining multiple pulse sequences into a “supersequence” when relaxation is slow (NOAH) (9Claridge T.D.W. Kupče E. NOAH: NMR supersequences for small molecule analysis and structure elucidation.Angew. Chem. 2017; 56: 11779-11783Crossref Scopus (49) Google Scholar), Schiavina et a1. (6Schiavina H. Murrali M.G. Felli I.C. et al.Taking simultaneous snapshots of intrinsically disordered proteins in action.Biophys. J. 2019; 117: 46-55Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar) shift the emphasis to direct 13C and 15N detection to escape from the limitation caused by the exchange of labile protons in IDR in physiological conditions, such as the ones encountered when proteins are studied inside living cells or when following physiological posttranslational modifications. Implementation is conceptually straightforward, just taking care to preserve 13C carbonyl magnetization at the beginning of the CON experiment. Multiple scans of shorter experiments can be introduced in the waiting time of a single CON scan to improve the signal/noise ratio of less-sensitive experiments. Further improvements in the optimization of NMR acquisition are expected from the introduction of nonuniform sampling schemes in the various indirect detection steps, although residual cross talk between the embedded experiments should be carefully scrutinized. Improved experimental methods to study intrinsically disordered proteins parallel the increased awareness about these still poorly understood but essential components of eukaryotic regulatory systems. The frontier is moving, as it should, from technical issues to the conceptual problem of understanding how information is encoded in conformational ensembles and fuzzy complexes (10Arbesú M. Iruela G. Pons M. et al.Intramolecular fuzzy interactions involving intrinsically disordered domains.Front. Mol. Biosci. 2018; 5: 39Crossref PubMed Scopus (46) Google Scholar) expanding the paradigm from structure-function to a much wider one linking information to function, of which the classical structure-function paradigm is a particular case. I thank Dr. Marga Gairí for helpful comments. Work in the Pons Laboratory is supported by the Spanish Ministerio de Ciencia, Innovación y Universidades, cofinanced by Fonds Européen de Développement Économique et Régional (BIO2016-78006R) and uses the Spanish large-scale NMR facility Red de Laboratorios de RMN de Biomoléculas. Taking Simultaneous Snapshots of Intrinsically Disordered Proteins in ActionSchiavina et al.Biophysical JournalMay 22, 2019In BriefIntrinsically disordered proteins (IDPs) as well as intrinsically disordered regions (IDRs) of complex protein machineries have recently been recognized as key players in many cellular functions. NMR represents a unique tool to access atomic resolution structural and dynamic information on highly flexible IDPs/IDRs. Improvements in instrumental sensitivity made heteronuclear direct detection possible for biomolecular NMR applications. The CON experiment has become one of the most useful NMR experiments to get a snapshot of an IDP/IDR in conditions approaching physiological ones. 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• W2952669678 title "A “Russian Doll” Approach to More Efficient Acquisition of IDP NMR Spectra" @default.
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