From Sequence and Forces to Structure, Function, and Evolution of Intrinsically Disordered Proteins

Overview

Journal Structure

Publisher Cell Press

Specialties Biochemistry
Biotechnology
Cell Biology
Molecular Biology

Date 2013 Sep 10

PMID 24010708

Citations 123

Authors

Julie D Forman-Kay

Tanja Mittag

Affiliations

Soon will be listed here.

Abstract

Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due to the inapplicability of standard methods for characterization of folded proteins as well as their deviation from the dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred the growing acceptance of the importance of IDPs and the development of new tools for studying their structure, dynamics, and function. The interplay of folded and disordered domains or regions for function and the existence of a continuum of protein states with respect to conformational energetics, motional timescales, and compactness are shaping a unified understanding of structure-dynamics-disorder/function relationships. In the 20(th) anniversary of Structure, we provide a historical perspective on the investigation of IDPs and summarize the sequence features and physical forces that underlie their unique structural, functional, and evolutionary properties.

Citing Articles

HP0135 Is a Small Lipoprotein That Has a Role in Outer Membrane Stability.

Nguyen D, Ivester R, Rosinke K, Hoover T Molecules. 2025; 30(2).

PMID: 39860075 PMC: 11768039. DOI: 10.3390/molecules30020204.

Scale-free Spatio-temporal Correlations in Conformational Fluctuations of Intrinsically Disordered Proteins.

Song H, Cui J, Hu G, Xiong L, Wutthinitikornkit Y, Lei H Adv Sci (Weinh). 2025; 12(9):e2412989.

PMID: 39807013 PMC: 11884614. DOI: 10.1002/advs.202412989.

Proteins Associated with Neurodegenerative Diseases: Link to DNA Repair.

Khodyreva S, Dyrkheeva N, Lavrik O Biomedicines. 2025; 12(12.

PMID: 39767715 PMC: 11673744. DOI: 10.3390/biomedicines12122808.

Functional specificity in biomolecular condensates revealed by genetic complementation.

Sabari B, Hyman A, Hnisz D Nat Rev Genet. 2024; .

PMID: 39433596 DOI: 10.1038/s41576-024-00780-4.

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.

References

Smagghe B, Huang P, Ban Y, Baker D, Springer T . Modulation of integrin activation by an entropic spring in the {beta}-knee. J Biol Chem. 2010; 285(43):32954-32966. PMC: 2963379. DOI: 10.1074/jbc.M110.145177. View

Uversky V . Targeting intrinsically disordered proteins in neurodegenerative and protein dysfunction diseases: another illustration of the D(2) concept. Expert Rev Proteomics. 2010; 7(4):543-64. PMC: 3371274. DOI: 10.1586/epr.10.36. View

Furt F, Moreau P . Importance of lipid metabolism for intracellular and mitochondrial membrane fusion/fission processes. Int J Biochem Cell Biol. 2009; 41(10):1828-36. DOI: 10.1016/j.biocel.2009.02.005. View

Richards F . Whatever happened to the fun? An autobiographical investigation. Annu Rev Biophys Biomol Struct. 1997; 26:1-25. DOI: 10.1146/annurev.biophys.26.1.1. View

Oates M, Romero P, Ishida T, Ghalwash M, Mizianty M, Xue B . D²P²: database of disordered protein predictions. Nucleic Acids Res. 2012; 41(Database issue):D508-16. PMC: 3531159. DOI: 10.1093/nar/gks1226. View

Oldfield C, Meng J, Yang J, Yang M, Uversky V, Dunker A . Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners. BMC Genomics. 2008; 9 Suppl 1:S1. PMC: 2386051. DOI: 10.1186/1471-2164-9-S1-S1. View

Mittag T, Orlicky S, Choy W, Tang X, Lin H, Sicheri F . Dynamic equilibrium engagement of a polyvalent ligand with a single-site receptor. Proc Natl Acad Sci U S A. 2008; 105(46):17772-7. PMC: 2582940. DOI: 10.1073/pnas.0809222105. View

Li P, Banjade S, Cheng H, Kim S, Chen B, Guo L . Phase transitions in the assembly of multivalent signalling proteins. Nature. 2012; 483(7389):336-40. PMC: 3343696. DOI: 10.1038/nature10879. View

Williams R, Obradovi Z, Mathura V, Braun W, Garner E, Young J . The protein non-folding problem: amino acid determinants of intrinsic order and disorder. Pac Symp Biocomput. 2001; :89-100. DOI: 10.1142/9789814447362_0010. View

10.

Buljan M, Chalancon G, Dunker A, Bateman A, Balaji S, Fuxreiter M . Alternative splicing of intrinsically disordered regions and rewiring of protein interactions. Curr Opin Struct Biol. 2013; 23(3):443-50. DOI: 10.1016/j.sbi.2013.03.006. View

11.

Tompa P . Hydrogel formation by multivalent IDPs: A reincarnation of the microtrabecular lattice?. Intrinsically Disord Proteins. 2017; 1(1):e24068. PMC: 5424804. DOI: 10.4161/idp.24068. View

12.

Fink A . Natively unfolded proteins. Curr Opin Struct Biol. 2005; 15(1):35-41. DOI: 10.1016/j.sbi.2005.01.002. View

13.

Marsh J, Dancheck B, Ragusa M, Allaire M, Forman-Kay J, Peti W . Structural diversity in free and bound states of intrinsically disordered protein phosphatase 1 regulators. Structure. 2010; 18(9):1094-103. PMC: 2936704. DOI: 10.1016/j.str.2010.05.015. View

14.

Hilser V, Thompson E . Intrinsic disorder as a mechanism to optimize allosteric coupling in proteins. Proc Natl Acad Sci U S A. 2007; 104(20):8311-5. PMC: 1895946. DOI: 10.1073/pnas.0700329104. View

15.

Mao A, Crick S, Vitalis A, Chicoine C, Pappu R . Net charge per residue modulates conformational ensembles of intrinsically disordered proteins. Proc Natl Acad Sci U S A. 2010; 107(18):8183-8. PMC: 2889596. DOI: 10.1073/pnas.0911107107. View

16.

Huang Y, Liu Z . Kinetic advantage of intrinsically disordered proteins in coupled folding-binding process: a critical assessment of the "fly-casting" mechanism. J Mol Biol. 2009; 393(5):1143-59. DOI: 10.1016/j.jmb.2009.09.010. View

17.

Meszaros B, Simon I, Dosztanyi Z . The expanding view of protein-protein interactions: complexes involving intrinsically disordered proteins. Phys Biol. 2011; 8(3):035003. DOI: 10.1088/1478-3975/8/3/035003. View

18.

Marsh J, Forman-Kay J . Ensemble modeling of protein disordered states: experimental restraint contributions and validation. Proteins. 2011; 80(2):556-72. DOI: 10.1002/prot.23220. View

19.

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

20.

Milles S, Lemke E . Single molecule study of the intrinsically disordered FG-repeat nucleoporin 153. Biophys J. 2011; 101(7):1710-9. PMC: 3183753. DOI: 10.1016/j.bpj.2011.08.025. View