Structural Characterization of Intrinsically Disordered Proteins by NMR Spectroscopy

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2013 Sep 7

PMID 24008243

Citations 78

Authors

Simone Kosol

Sara Contreras-Martos

Cesyen Cedeno

Peter Tompa

Affiliations

Soon will be listed here.

Abstract

Recent advances in NMR methodology and techniques allow the structural investigation of biomolecules of increasing size with atomic resolution. NMR spectroscopy is especially well-suited for the study of intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) which are in general highly flexible and do not have a well-defined secondary or tertiary structure under functional conditions. In the last decade, the important role of IDPs in many essential cellular processes has become more evident as the lack of a stable tertiary structure of many protagonists in signal transduction, transcription regulation and cell-cycle regulation has been discovered. The growing demand for structural data of IDPs required the development and adaption of methods such as 13C-direct detected experiments, paramagnetic relaxation enhancements (PREs) or residual dipolar couplings (RDCs) for the study of 'unstructured' molecules in vitro and in-cell. The information obtained by NMR can be processed with novel computational tools to generate conformational ensembles that visualize the conformations IDPs sample under functional conditions. Here, we address NMR experiments and strategies that enable the generation of detailed structural models of IDPs.

Citing Articles

Quantitative Interpretation of Transverse Spin Relaxation by Translational Diffusion in Liquids.

Okuno Y J Phys Chem B. 2025; 129(9):2537-2545.

PMID: 39977431 PMC: 11891894. DOI: 10.1021/acs.jpcb.4c08225.

Acetylation-Dependent Compaction of the Histone H4 Tail Ensemble.

Dewing S, Phan T, Kraft E, Mittal J, Showalter S J Phys Chem B. 2024; 128(43):10636-10649.

PMID: 39437158 PMC: 11533190. DOI: 10.1021/acs.jpcb.4c05701.

Computational Methods to Investigate Intrinsically Disordered Proteins and their Complexes.

Liu Z, Tsanai M, Zhang O, Forman-Kay J, Head-Gordon T ArXiv. 2024; .

PMID: 39279844 PMC: 11398552.

Exploring the Functional Landscape of the p53 Regulatory Domain: The Stabilizing Role of Post-Translational Modifications.

Bakker M, Svensson O, So Rensen H, Skepo M J Chem Theory Comput. 2024; 20(14):5842-5853.

PMID: 38973087 PMC: 11270737. DOI: 10.1021/acs.jctc.4c00570.

Experimental methods to study the structure and dynamics of intrinsically disordered regions in proteins.

Maiti S, Singh A, Maji T, Saibo N, De S Curr Res Struct Biol. 2024; 7:100138.

PMID: 38707546 PMC: 11068507. DOI: 10.1016/j.crstbi.2024.100138.

References

Zawadzka-Kazimierczuk A, Kozminski W, Sanderova H, Krasny L . High dimensional and high resolution pulse sequences for backbone resonance assignment of intrinsically disordered proteins. J Biomol NMR. 2012; 52(4):329-37. PMC: 3315646. DOI: 10.1007/s10858-012-9613-x. View

Smith L, Bolin K, Schwalbe H, MacArthur M, Thornton J, Dobson C . Analysis of main chain torsion angles in proteins: prediction of NMR coupling constants for native and random coil conformations. J Mol Biol. 1996; 255(3):494-506. DOI: 10.1006/jmbi.1996.0041. View

Bertini I, Felli I, Gonnelli L, Vasantha Kumar M, Pierattelli R . High-resolution characterization of intrinsic disorder in proteins: expanding the suite of (13)C-detected NMR spectroscopy experiments to determine key observables. Chembiochem. 2012; 12(15):2347-52. DOI: 10.1002/cbic.201100406. View

Eliezer D, Barre P, Kobaslija M, Chan D, Li X, Heend L . Residual structure in the repeat domain of tau: echoes of microtubule binding and paired helical filament formation. Biochemistry. 2005; 44(3):1026-36. DOI: 10.1021/bi048953n. View

Pancsa R, Tompa P . Structural disorder in eukaryotes. PLoS One. 2012; 7(4):e34687. PMC: 3320622. DOI: 10.1371/journal.pone.0034687. View

Banci L, Barbieri L, Bertini I, Luchinat E, Secci E, Zhao Y . Atomic-resolution monitoring of protein maturation in live human cells by NMR. Nat Chem Biol. 2013; 9(5):297-9. PMC: 4017183. DOI: 10.1038/nchembio.1202. View

Bermel W, Bertini I, Felli I, Lee Y, Luchinat C, Pierattelli R . Protonless NMR experiments for sequence-specific assignment of backbone nuclei in unfolded proteins. J Am Chem Soc. 2006; 128(12):3918-9. DOI: 10.1021/ja0582206. View

Burz D, Dutta K, Cowburn D, Shekhtman A . In-cell NMR for protein-protein interactions (STINT-NMR). Nat Protoc. 2007; 1(1):146-52. DOI: 10.1038/nprot.2006.23. View

Otten R, Wood K, Mulder F . Comprehensive determination of (3)J (HNHalpha) for unfolded proteins using (13)C'-resolved spin-echo difference spectroscopy. J Biomol NMR. 2009; 45(4):343-9. PMC: 2777233. DOI: 10.1007/s10858-009-9382-3. View

10.

Flaugh S, Lumb K . Effects of macromolecular crowding on the intrinsically disordered proteins c-Fos and p27(Kip1). Biomacromolecules. 2001; 2(2):538-40. DOI: 10.1021/bm015502z. View

11.

Theillet F, Smet-Nocca C, Liokatis S, Thongwichian R, Kosten J, Yoon M . Cell signaling, post-translational protein modifications and NMR spectroscopy. J Biomol NMR. 2012; 54(3):217-36. PMC: 4939263. DOI: 10.1007/s10858-012-9674-x. View

12.

Permi P, Kilpelainen I, Annila A . Determination of backbone angle psi in proteins using a TROSY-based alpha/beta-HN(CO)CA-J experiment. J Magn Reson. 2000; 146(2):255-9. DOI: 10.1006/jmre.2000.2157. View

13.

Fischer M, Losonczi J, Weaver J, Prestegard J . Domain orientation and dynamics in multidomain proteins from residual dipolar couplings. Biochemistry. 1999; 38(28):9013-22. DOI: 10.1021/bi9905213. View

14.

Akoury E, Gajda M, Pickhardt M, Biernat J, Soraya P, Griesinger C . Inhibition of tau filament formation by conformational modulation. J Am Chem Soc. 2013; 135(7):2853-62. DOI: 10.1021/ja312471h. View

15.

Prestegard J, Bougault C, Kishore A . Residual dipolar couplings in structure determination of biomolecules. Chem Rev. 2004; 104(8):3519-40. DOI: 10.1021/cr030419i. View

16.

Vendruscolo M . Determination of conformationally heterogeneous states of proteins. Curr Opin Struct Biol. 2007; 17(1):15-20. DOI: 10.1016/j.sbi.2007.01.002. View

17.

Wells M, Tidow H, Rutherford T, Markwick P, Jensen M, Mylonas E . Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain. Proc Natl Acad Sci U S A. 2008; 105(15):5762-7. PMC: 2311362. DOI: 10.1073/pnas.0801353105. View

18.

Babu M, van der Lee R, Sanchez de Groot N, Gsponer J . Intrinsically disordered proteins: regulation and disease. Curr Opin Struct Biol. 2011; 21(3):432-40. DOI: 10.1016/j.sbi.2011.03.011. View

19.

Narayanan R, Durr U, Bibow S, Biernat J, Mandelkow E, Zweckstetter M . Automatic assignment of the intrinsically disordered protein Tau with 441-residues. J Am Chem Soc. 2010; 132(34):11906-7. DOI: 10.1021/ja105657f. View

20.

Palmer 3rd A . NMR characterization of the dynamics of biomacromolecules. Chem Rev. 2004; 104(8):3623-40. DOI: 10.1021/cr030413t. View