Dynamic Conformational Flexibility and Molecular Interactions of Intrinsically Disordered Proteins

Overview

Journal J Biosci

Specialties Biochemistry
Biology

Date 2020 Feb 6

PMID 32020911

Citations 7

Authors

Anil Bhattarai

Isaac Arnold Emerson

Affiliations

Soon will be listed here.

Abstract

Intrinsically disordered proteins (IDPs) are highly flexible and undergo disorder to order transition upon binding. They are highly abundant in human proteomes and play critical roles in cell signaling and regulatory processes. This review mainly focuses on the dynamics of disordered proteins including their conformational heterogeneity, protein-protein interactions, and the phase transition of biomolecular condensates that are central to various biological functions. Besides, the role of RNA-mediated chaperones in protein folding and stability of IDPs were also discussed. Finally, we explored the dynamic binding interface of IDPs as novel therapeutic targets and the effect of small molecules on their interactions.

Citing Articles

Conservation of OFD1 Protein Motifs: Implications for Discovery of Novel Interactors and the OFD1 Function.

Jagodzik P, Zietkiewicz E, Bukowy-Bieryllo Z Int J Mol Sci. 2025; 26(3).

PMID: 39940934 PMC: 11818881. DOI: 10.3390/ijms26031167.

Genome-Wide Characterization of Wholly Disordered Proteins in .

Long W, Zhao L, Yang H, Yang X, Bai Y, Xue X Int J Mol Sci. 2025; 26(3).

PMID: 39940886 PMC: 11817481. DOI: 10.3390/ijms26031117.

Development of a Cell-Based AlphaLISA Assay for High-Throughput Screening for Small Molecule Proteasome Modulators.

Staerz S, Lisabeth E, Njomen E, Dexheimer T, Neubig R, Tepe J ACS Omega. 2023; 8(17):15650-15659.

PMID: 37151549 PMC: 10157846. DOI: 10.1021/acsomega.3c01158.

The Role of Intrinsically Disordered Proteins in Liquid-Liquid Phase Separation during Calcium Carbonate Biomineralization.

Tarczewska A, Bielak K, Zoglowek A, Soltys K, Dobryszycki P, Ozyhar A Biomolecules. 2022; 12(9).

PMID: 36139105 PMC: 9496343. DOI: 10.3390/biom12091266.

Immunoinformatic analysis of the whole proteome for vaccine design: An application to .

Soto L, Romani A, Jimenez-Avalos G, Silva Y, Ordinola-Ramirez C, Lopez Lapa R Front Immunol. 2022; 13:942907.

PMID: 36110855 PMC: 9469472. DOI: 10.3389/fimmu.2022.942907.

References

Balch W, Morimoto R, Dillin A, Kelly J . Adapting proteostasis for disease intervention. Science. 2008; 319(5865):916-9. DOI: 10.1126/science.1141448. View

Dosnon M, Bonetti D, Morrone A, Erales J, di Silvio E, Longhi S . Demonstration of a folding after binding mechanism in the recognition between the measles virus NTAIL and X domains. ACS Chem Biol. 2014; 10(3):795-802. DOI: 10.1021/cb5008579. View

Uversky V, Dunker A . Multiparametric analysis of intrinsically disordered proteins: looking at intrinsic disorder through compound eyes. Anal Chem. 2012; 84(5):2096-104. DOI: 10.1021/ac203096k. View

Prabhudesai S, Sinha S, Attar A, Kotagiri A, Fitzmaurice A, Lakshmanan R . A novel "molecular tweezer" inhibitor of α-synuclein neurotoxicity in vitro and in vivo. Neurotherapeutics. 2012; 9(2):464-76. PMC: 3337029. DOI: 10.1007/s13311-012-0105-1. View

Johnson T, Ermolieff J, Jirousek M . Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov. 2002; 1(9):696-709. DOI: 10.1038/nrd895. View

Docter B, Horowitz S, Gray M, Jakob U, Bardwell J . Do nucleic acids moonlight as molecular chaperones?. Nucleic Acids Res. 2016; 44(10):4835-45. PMC: 4889950. DOI: 10.1093/nar/gkw291. View

Kosol S, Contreras-Martos S, Cedeno C, Tompa P . Structural characterization of intrinsically disordered proteins by NMR spectroscopy. Molecules. 2013; 18(9):10802-28. PMC: 6269831. DOI: 10.3390/molecules180910802. View

OHare E, Scopes D, Kim E, Palmer P, Spanswick D, McMahon B . Novel 5-aryloxypyrimidine SEN1576 as a candidate for the treatment of Alzheimer's disease. Int J Neuropsychopharmacol. 2013; 17(1):117-26. DOI: 10.1017/S1461145713000886. View

Kim J, Choi H, Seong B . The folding competence of HIV-1 Tat mediated by interaction with TAR RNA. RNA Biol. 2017; 14(7):926-937. PMC: 5546542. DOI: 10.1080/15476286.2017.1311455. View

10.

Uversky V, Oldfield C, Dunker A . Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys. 2008; 37:215-46. DOI: 10.1146/annurev.biophys.37.032807.125924. View

11.

Fukuchi S, Sakamoto S, Nobe Y, Murakami S, Amemiya T, Hosoda K . IDEAL: Intrinsically Disordered proteins with Extensive Annotations and Literature. Nucleic Acids Res. 2011; 40(Database issue):D507-11. PMC: 3245138. DOI: 10.1093/nar/gkr884. View

12.

Hartl F, Bracher A, Hayer-Hartl M . Molecular chaperones in protein folding and proteostasis. Nature. 2011; 475(7356):324-32. DOI: 10.1038/nature10317. View

13.

Graewert M, Svergun D . Impact and progress in small and wide angle X-ray scattering (SAXS and WAXS). Curr Opin Struct Biol. 2013; 23(5):748-54. DOI: 10.1016/j.sbi.2013.06.007. View

14.

Piovesan D, Tabaro F, Micetic I, Necci M, Quaglia F, Oldfield C . DisProt 7.0: a major update of the database of disordered proteins. Nucleic Acids Res. 2016; 45(D1):D219-D227. PMC: 5210544. DOI: 10.1093/nar/gkw1056. View

15.

Nott T, Petsalaki E, Farber P, Jervis D, Fussner E, Plochowietz A . Phase transition of a disordered nuage protein generates environmentally responsive membraneless organelles. Mol Cell. 2015; 57(5):936-947. PMC: 4352761. DOI: 10.1016/j.molcel.2015.01.013. View

16.

Martin E, Mittag T . Relationship of Sequence and Phase Separation in Protein Low-Complexity Regions. Biochemistry. 2018; 57(17):2478-2487. PMC: 6476794. DOI: 10.1021/acs.biochem.8b00008. View

17.

Fahmi M, Ito M . Evolutionary Approach of Intrinsically Disordered CIP/KIP Proteins. Sci Rep. 2019; 9(1):1575. PMC: 6367352. DOI: 10.1038/s41598-018-37917-5. View

18.

Espinoza-Fonseca L . Reconciling binding mechanisms of intrinsically disordered proteins. Biochem Biophys Res Commun. 2009; 382(3):479-82. DOI: 10.1016/j.bbrc.2009.02.151. View

19.

Schad E, Ficho E, Pancsa R, Simon I, Dosztanyi Z, Meszaros B . DIBS: a repository of disordered binding sites mediating interactions with ordered proteins. Bioinformatics. 2018; 34(3):535-537. PMC: 5860366. DOI: 10.1093/bioinformatics/btx640. View

20.

Jankovic J, Goodman I, Safirstein B, Marmon T, Schenk D, Koller M . Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients With Parkinson Disease: A Randomized Clinical Trial. JAMA Neurol. 2018; 75(10):1206-1214. PMC: 6233845. DOI: 10.1001/jamaneurol.2018.1487. View