The Contribution of Intrinsically Disordered Regions to Protein Function, Cellular Complexity, and Human Disease

Overview

Journal Biochem Soc Trans

Specialty Biochemistry

Date 2016 Dec 3

PMID 27911701

Citations 192

Authors

M Madan Babu

Affiliations

Soon will be listed here.

Abstract

In the 1960s, Christian Anfinsen postulated that the unique three-dimensional structure of a protein is determined by its amino acid sequence. This work laid the foundation for the sequence-structure-function paradigm, which states that the sequence of a protein determines its structure, and structure determines function. However, a class of polypeptide segments called intrinsically disordered regions does not conform to this postulate. In this review, I will first describe established and emerging ideas about how disordered regions contribute to protein function. I will then discuss molecular principles by which regulatory mechanisms, such as alternative splicing and asymmetric localization of transcripts that encode disordered regions, can increase the functional versatility of proteins. Finally, I will discuss how disordered regions contribute to human disease and the emergence of cellular complexity during organismal evolution.

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References

Weatheritt R, Gibson T . Linear motifs: lost in (pre)translation. Trends Biochem Sci. 2012; 37(8):333-41. DOI: 10.1016/j.tibs.2012.05.001. View

Seet B, Dikic I, Zhou M, Pawson T . Reading protein modifications with interaction domains. Nat Rev Mol Cell Biol. 2006; 7(7):473-83. DOI: 10.1038/nrm1960. View

Weatheritt R, Davey N, Gibson T . Linear motifs confer functional diversity onto splice variants. Nucleic Acids Res. 2012; 40(15):7123-31. PMC: 3424572. DOI: 10.1093/nar/gks442. View

Abascal F, Ezkurdia I, Rodriguez-Rivas J, Rodriguez J, Del Pozo A, Vazquez J . Alternatively Spliced Homologous Exons Have Ancient Origins and Are Highly Expressed at the Protein Level. PLoS Comput Biol. 2015; 11(6):e1004325. PMC: 4465641. DOI: 10.1371/journal.pcbi.1004325. View

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

Vacic V, Iakoucheva L . Disease mutations in disordered regions--exception to the rule?. Mol Biosyst. 2011; 8(1):27-32. PMC: 3307532. DOI: 10.1039/c1mb05251a. View

Toretsky J, Wright P . Assemblages: functional units formed by cellular phase separation. J Cell Biol. 2014; 206(5):579-88. PMC: 4151146. DOI: 10.1083/jcb.201404124. View

Romero P, Zaidi S, Fang Y, Uversky V, Radivojac P, Oldfield C . Alternative splicing in concert with protein intrinsic disorder enables increased functional diversity in multicellular organisms. Proc Natl Acad Sci U S A. 2006; 103(22):8390-5. PMC: 1482503. DOI: 10.1073/pnas.0507916103. View

Ward J, Sodhi J, McGuffin L, Buxton B, Jones D . Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol. 2004; 337(3):635-45. DOI: 10.1016/j.jmb.2004.02.002. View

10.

Sanchez de Groot N, Torrent M, Villar-Pique A, Lang B, Ventura S, Gsponer J . Evolutionary selection for protein aggregation. Biochem Soc Trans. 2012; 40(5):1032-7. DOI: 10.1042/BST20120160. View

11.

Mitrea D, Kriwacki R . Phase separation in biology; functional organization of a higher order. Cell Commun Signal. 2016; 14:1. PMC: 4700675. DOI: 10.1186/s12964-015-0125-7. View

12.

Wu H, Fuxreiter M . The Structure and Dynamics of Higher-Order Assemblies: Amyloids, Signalosomes, and Granules. Cell. 2016; 165(5):1055-1066. PMC: 4878688. DOI: 10.1016/j.cell.2016.05.004. View

13.

Liu B, Chia D, Csizmok V, Farber P, Forman-Kay J, Gradinaru C . The effect of intrachain electrostatic repulsion on conformational disorder and dynamics of the Sic1 protein. J Phys Chem B. 2014; 118(15):4088-97. DOI: 10.1021/jp500776v. View

14.

Wright P, Dyson H . Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol. 1999; 293(2):321-31. DOI: 10.1006/jmbi.1999.3110. View

15.

Uyar B, Weatheritt R, Dinkel H, Davey N, Gibson T . Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?. Mol Biosyst. 2014; 10(10):2626-42. PMC: 4306509. DOI: 10.1039/c4mb00290c. View

16.

Van Roey K, Dinkel H, Weatheritt R, Gibson T, Davey N . The switches.ELM resource: a compendium of conditional regulatory interaction interfaces. Sci Signal. 2013; 6(269):rs7. DOI: 10.1126/scisignal.2003345. View

17.

Babu M, Kriwacki R, Pappu R . Structural biology. Versatility from protein disorder. Science. 2012; 337(6101):1460-1. DOI: 10.1126/science.1228775. View

18.

Jung H, Gkogkas C, Sonenberg N, Holt C . Remote control of gene function by local translation. Cell. 2014; 157(1):26-40. PMC: 3988848. DOI: 10.1016/j.cell.2014.03.005. View

19.

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

20.

Gsponer J, Babu M . Cellular strategies for regulating functional and nonfunctional protein aggregation. Cell Rep. 2012; 2(5):1425-37. PMC: 3607227. DOI: 10.1016/j.celrep.2012.09.036. View