Abstract
This mini-review represents a brief, disorder-centric consideration of the interplay between order and disorder in proteins. The goal here is to show that inside the cell, folding, non-folding, and misfolding of proteins are interlinked on multiple levels. This is evidenced by the highly heterogeneous spatio-temporal structural organization of a protein molecule, where one can find differently (dis)ordered components that can undergo local or global order-to-disorder and disorder-to-order transitions needed for functionality. This is further illustrated by the fact that at particular moments of their life, most notably during their synthesis and degradation, all proteins are at least partially disordered. In addition to these intrinsic forms of disorder, proteins are constantly facing extrinsic disorder, which is intrinsic disorder in their functional partners. All this comprises the multileveled protein disorder cycle.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alterovitz WL, Faraggi E, Oldfield CJ, Meng J, Xue B, Huang F, Romero P, Kloczkowski A, Uversky VN, Dunker AK (2020) Many-to-one binding by intrinsically disordered protein regions. Pac Symp Biocomput 25:159–170. https://doi.org/10.1142/9789811215636_0015
Bardwell JC, Jakob U (2012) Conditional disorder in chaperone action. Trends Biochem Sci 37(12):517–525. https://doi.org/10.1016/j.tibs.2012.08.006
Cheng Y, Oldfield CJ, Meng J, Romero P, Uversky VN, Dunker AK (2007) Mining alpha-helix-forming molecular recognition features with cross species sequence alignments. Biochemistry 46(47):13468–13477. https://doi.org/10.1021/bi7012273
Christensen LFB, Schafer N, Wolf-Perez A, Madsen DJ, Otzen DE (2019) Bacterial amyloids: biogenesis and biomaterials. Adv Exp Med Biol 1174:113–159. https://doi.org/10.1007/978-981-13-9791-2_4
Cortese MS, Uversky VN, Dunker AK (2008) Intrinsic disorder in scaffold proteins: getting more from less. Prog Biophys Mol Biol 98(1):85–106. https://doi.org/10.1016/j.pbiomolbio.2008.05.007
Creamer T (2013) Transient disorder: calcineurin as an example. Intrin Disordered Proteins 1(1):e26412. https://doi.org/10.4161/idp.26412
Daskalov A, El Mammeri N, Lends A, Shenoy J, Lamon G, Fichou Y, Saad A, Martinez D, Morvan E, Berbon M, Grelard A, Kauffmann B, Ferber M, Bardiaux B, Habenstein B, Saupe SJ, Loquet A (2021) Structures of pathological and functional amyloids and prions, a solid-state NMR perspective. Front Mol Neurosci 14:670513. https://doi.org/10.3389/fnmol.2021.670513
DeForte S, Uversky VN (2016) Order, disorder, and everything in between. Molecules 21(8):1090. https://doi.org/10.3390/molecules21081090
Deshmukh M, Evans ML, Chapman MR (2018) Amyloid by design: intrinsic regulation of microbial amyloid assembly. J Mol Biol 430(20):3631–3641. https://doi.org/10.1016/j.jmb.2018.07.007
Dosztányi Z, Csizmok V, Tompa P, Simon I (2005) IUPred: web server for the prediction of intrinsically unstructured regions of proteins based on estimated energy content. Bioinformatics 21(16):3433–3434. https://doi.org/10.1093/bioinformatics/bti541
Dosztanyi Z, Chen J, Dunker AK, Simon I, Tompa P (2006) Disorder and sequence repeats in hub proteins and their implications for network evolution. J Proteome Res 5(11):2985–2995. https://doi.org/10.1021/pr060171o
Dunker AK, Obradovic Z (2001) The protein trinity–linking function and disorder. Nat Biotechnol 19(9):805–806. https://doi.org/10.1038/nbt0901-805
Dunker AK, Obradovic Z, Romero P, Garner EC, Brown CJ (2000) Intrinsic protein disorder in complete genomes. Genome Inform Ser Workshop Genome Inform 11:161–171. https://doi.org/10.11234/gi1990.11.161
Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, Oldfield CJ, Campen AM, Ratliff CM, Hipps KW, Ausio J, Nissen MS, Reeves R, Kang C, Kissinger CR, Bailey RW, Griswold MD, Chiu W, Garner EC, Obradovic Z (2001) Intrinsically disordered protein. J Mol Graph Model 19(1):26–59. https://doi.org/10.1016/s1093-3263(00)00138-8
Dunker AK, Brown CJ, Lawson JD, Iakoucheva LM, Obradovic Z (2002a) Intrinsic disorder and protein function. Biochemistry 41(21):6573–6582. https://doi.org/10.1021/bi012159+
Dunker AK, Brown CJ, Obradovic Z (2002b) Identification and functions of usefully disordered proteins. Adv Protein Chem 62:25–49. https://doi.org/10.1016/s0065-3233(02)62004-2
Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN (2005) Flexible nets: the roles of intrinsic disorder in protein interaction networks. FEBS J 272(20):5129–5148. https://doi.org/10.1111/j.1742-4658.2005.04948.x
Dunker AK, Babu MM, Barbar E, Blackledge M, Bondos SE, Dosztányi Z, Dyson HJ, Forman-Kay J, Fuxreiter M, Gsponer J, Han K-H, Jones DT, Longhi S, Metallo SJ, Nishikawa K, Nussinov R, Obradovic Z, Pappu R, Rost B, Selenko P, Subramaniam V, Sussman JL, Tompa P, Uversky VN (2013) What’s in a name? Why these proteins are intrinsically disordered. Intrinsically Disord Proteins 1(1):e24157. https://doi.org/10.4161/idp.24157
Dunker AK, Bondos SE, Huang F, Oldfield CJ (2015) Intrinsically disordered proteins and multicellular organisms. Semin Cell Dev Biol 37:44–55. https://doi.org/10.1016/j.semcdb.2014.09.025
Dunker AK, Oldfield CJ, Meng J, Romero P, Yang JY, Chen JW, Vacic V, Obradovic Z, Uversky VN (2008a) The unfoldomics decade: an update on intrinsically disordered proteins. BMC Genomics 9(Suppl 2):S1. https://doi.org/10.1186/1471-2164-9-S2-S1
Dunker AK, Silman I, Uversky VN, Sussman JL (2008b) Function and structure of inherently disordered proteins. Curr Opin Struct Biol 18(6):756–764. https://doi.org/10.1016/j.sbi.2008.10.002
Dunker AK, Uversky VN (2008) Signal transduction via unstructured protein conduits. Nat Chem Biol 4(4):229–230. https://doi.org/10.1038/nchembio0408-229
Dyson HJ (2011) Expanding the proteome: disordered and alternatively folded proteins. Q Rev Biophys 44(4):467–518. https://doi.org/10.1017/S0033583511000060
Dyson HJ, Wright PE (2002) Coupling of folding and binding for unstructured proteins. Curr Opin Struct Biol 12(1):54–60. https://doi.org/10.1016/s0959-440x(02)00289-0
Dyson HJ, Wright PE (2005) Intrinsically unstructured proteins and their functions. Nat Rev Mol Cell Biol 6(3):197–208. https://doi.org/10.1038/Nrm1589
Ekman D, Light S, Bjorklund AK, Elofsson A (2006) What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? Genome Biol 7(6):R45. https://doi.org/10.1186/gb-2006-7-6-r45
Fisher CK, Stultz CM (2011) Constructing ensembles for intrinsically disordered proteins. Curr Opin Struct Biol 21(3):426–431. https://doi.org/10.1016/j.sbi.2011.04.001
Fonin AV, Darling AL, Kuznetsova IM, Turoverov KK, Uversky VN (2019) Multi-functionality of proteins involved in GPCR and G protein signaling: making sense of structure-function continuum with intrinsic disorder-based proteoforms. Cell Mol Life Sci. https://doi.org/10.1007/s00018-019-03276-1
Fontana A, Fassina G, Vita C, Dalzoppo D, Zamai M, Zambonin M (1986) Correlation between sites of limited proteolysis and segmental mobility in thermolysin. Biochemistry 25(8):1847–1851. https://doi.org/10.1021/bi00356a001
Fontana A, Polverino de Laureto P, De Filippis V, Scaramella E, Zambonin M (1997a) Probing the partly folded states of proteins by limited proteolysis. Fold Des 2(2):R17-26. https://doi.org/10.1016/S1359-0278(97)00010-2
Fontana A, Polverinode Laureto P, De Phillips V (1993) Molecular aspects of proteolysis of globular proteins. In: van den Tweel W, Harder A, Buitelear M (eds) Protein stability and stabilization. Elsevier Science, Amsterdam, pp 101–110. https://doi.org/10.1016/B978-0-444-89372-7.50017-8
Fontana A, Zambonin M, Polverino de Laureto P, De Filippis V, Clementi A, Scaramella E (1997b) Probing the conformational state of apomyoglobin by limited proteolysis. J Mol Biol 266(2):223–230. https://doi.org/10.1006/jmbi.1996.0787
Fuxreiter M (2020) Classifying the Binding Modes of Disordered Proteins. Int J Mol Sci 21(22):8615. https://doi.org/10.3390/ijms21228615
Fuxreiter M, Tompa P (2012) Fuzzy complexes: a more stochastic view of protein function. Adv Exp Med Biol 725:1–14. https://doi.org/10.1007/978-1-4614-0659-4_1
Gabashvili IS, Gregory ST, Valle M, Grassucci R, Worbs M, Wahl MC, Dahlberg AE, Frank J (2001) The polypeptide tunnel system in the ribosome and its gating in erythromycin resistance mutants of L4 and L22. Mol Cell 8(1):181–188. https://doi.org/10.1016/s1097-2765(01)00293-3
Gunasekaran K, Tsai CJ, Nussinov R (2004) Analysis of ordered and disordered protein complexes reveals structural features discriminating between stable and unstable monomers. J Mol Biol 341(5):1327–1341. https://doi.org/10.1016/j.jmb.2004.07.002
Haynes C, Oldfield CJ, Ji F, Klitgord N, Cusick ME, Radivojac P, Uversky VN, Vidal M, Iakoucheva LM (2006) Intrinsic disorder is a common feature of hub proteins from four eukaryotic interactomes. PLoS Comput Biol 2(8):e100. https://doi.org/10.1371/journal.pcbi.0020100
Hsu WL, Oldfield C, Meng J, Huang F, Xue B, Uversky VN, Romero P, Dunker AK (2012) Intrinsic protein disorder and protein-protein interactions. Pac Symp Biocomput:116–127. https://doi.org/10.1142/9789814366496_0012
Hsu WL, Oldfield CJ, Xue B, Meng J, Huang F, Romero P, Uversky VN, Dunker AK (2013) Exploring the binding diversity of intrinsically disordered proteins involved in one-to-many binding. Protein Sci 22(3):258–273. https://doi.org/10.1002/pro.2207
Iakoucheva LM, Kimzey AL, Masselon CD, Bruce JE, Garner EC, Brown CJ, Dunker AK, Smith RD, Ackerman EJ (2001) Identification of intrinsic order and disorder in the DNA repair protein XPA. Protein Sci 10(3):560–571. https://doi.org/10.1110/ps.29401
Jain N, Chapman MR (2019) Bacterial functional amyloids: Order from disorder. Biochim Biophys Acta Proteins Proteom 1867(10):954–960. https://doi.org/10.1016/j.bbapap.2019.05.010
Jakob U, Kriwacki RW, Uversky VN (2014) Conditionally and transiently disordered proteins: Awakening cryptic disorder to regulate protein function. Chem Rev 114(13):6779–6805. https://doi.org/10.1021/cr400459c
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature. https://doi.org/10.1038/s41586-021-03819-2
Kim YI, Burton RE, Burton BM, Sauer RT, Baker TA (2000) Dynamics of substrate denaturation and translocation by the ClpXP degradation machine. Mol Cell 5(4):639–648. https://doi.org/10.1016/s1097-2765(00)80243-9
Kovacs D, Rakacs M, Agoston B, Lenkey K, Semrad K, Schroeder R, Tompa P (2009) Janus chaperones: assistance of both RNA- and protein-folding by ribosomal proteins. FEBS Lett 583(1):88–92. https://doi.org/10.1016/j.febslet.2008.11.049
Kovacs D, Tompa P (2012) Diverse functional manifestations of intrinsic structural disorder in molecular chaperones. Biochem Soc Trans 40(5):963–968. https://doi.org/10.1042/BST20120108
Le Gall T, Romero PR, Cortese MS, Uversky VN, Dunker AK (2007) Intrinsic disorder in the Protein Data Bank. J Biomol Struct Dyn 24(4):325–342. https://doi.org/10.1080/07391102.2007.10507123
Lee C, Schwartz MP, Prakash S, Iwakura M, Matouschek A (2001) ATP-dependent proteases degrade their substrates by processively unraveling them from the degradation signal. Mol Cell 7(3):627–637. https://doi.org/10.1016/s1097-2765(01)00209-x
Levkovich SA, Gazit E, Laor Bar-Yosef D (2021) Two Decades of Studying Functional Amyloids in Microorganisms. Trends Microbiol 29(3):251–265. https://doi.org/10.1016/j.tim.2020.09.005
Meszaros B, Erdos G, Dosztanyi Z (2018) IUPred2A: context-dependent prediction of protein disorder as a function of redox state and protein binding. Nucleic Acids Res 46(W1):W329–W337. https://doi.org/10.1093/nar/gky384
Miskei M, Gregus A, Sharma R, Duro N, Zsolyomi F, Fuxreiter M (2017) Fuzziness enables context dependence of protein interactions. FEBS Lett 591(17):2682–2695. https://doi.org/10.1002/1873-3468.12762
Mohan A, Oldfield CJ, Radivojac P, Vacic V, Cortese MS, Dunker AK, Uversky VN (2006) Analysis of molecular recognition features (MoRFs). J Mol Biol 362(5):1043–1059. https://doi.org/10.1016/j.jmb.2006.07.087
Monzon AM, Necci M, Quaglia F, Walsh I, Zanotti G, Piovesan D, Tosatto SCE (2020) Experimentally Determined Long Intrinsically Disordered Protein Regions Are Now Abundant in the Protein Data Bank. Int J Mol Sci 21(12):4496. https://doi.org/10.3390/ijms21124496
Navon A, Goldberg AL (2001) Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Mol Cell 8(6):1339–1349. https://doi.org/10.1016/s1097-2765(01)00407-5
Oldfield CJ, Cheng Y, Cortese MS, Romero P, Uversky VN, Dunker AK (2005) Coupled folding and binding with alpha-helix-forming molecular recognition elements. Biochemistry 44(37):12454–12470. https://doi.org/10.1021/bi050736e
Oldfield CJ, Dunker AK (2014) Intrinsically disordered proteins and intrinsically disordered protein regions. Annu Rev Biochem 83:553–584. https://doi.org/10.1146/annurev-biochem-072711-164947
Oldfield CJ, Meng J, Yang JY, Yang MQ, Uversky VN, Dunker AK (2008) Flexible nets: disorder and induced fit in the associations of p53 and 14–3-3 with their partners. BMC Genomics 9(Suppl 1):S1. https://doi.org/10.1186/1471-2164-9-S1-S1
Pancsa R, Tompa P (2012) Structural disorder in eukaryotes. PLoS ONE 7(4):e34687. https://doi.org/10.1371/journal.pone.0034687
Patil A, Nakamura H (2006) Disordered domains and high surface charge confer hubs with the ability to interact with multiple proteins in interaction networks. FEBS Lett 580(8):2041–2045. https://doi.org/10.1016/j.febslet.2006.03.003
Peng K, Radivojac P, Vucetic S, Dunker AK, Obradovic Z (2006) Length-dependent prediction of protein intrinsic disorder. BMC Bioinformatics 7:208. https://doi.org/10.1186/1471-2105-7-208
Peng K, Vucetic S, Radivojac P, Brown CJ, Dunker AK, Obradovic Z (2005) Optimizing long intrinsic disorder predictors with protein evolutionary information. J Bioinform Comput Biol 3(1):35–60
Peng Z, Mizianty MJ, Kurgan L (2013a) Genome-scale prediction of proteins with long intrinsically disordered regions. Proteins. https://doi.org/10.1002/prot.24348
Peng Z, Oldfield CJ, Xue B, Mizianty MJ, Dunker AK, Kurgan L, Uversky VN (2013b) A creature with hundred of waggly tails: Intrinsically disordered proteins in ribosome. Cell Mol Life Sci in press
Peng Z, Yan J, Fan X, Mizianty MJ, Xue B, Wang K, Hu G, Uversky VN, Kurgan L (2015) Exceptionally abundant exceptions: comprehensive characterization of intrinsic disorder in all domains of life. Cell Mol Life Sci 72(1):137–151. https://doi.org/10.1007/s00018-014-1661-9
Prakash S, Matouschek A (2004) Protein unfolding in the cell. Trends Biochem Sci 29(11):593–600. https://doi.org/10.1016/j.tibs.2004.09.011
Prakash S, Tian L, Ratliff KS, Lehotzky RE, Matouschek A (2004) An unstructured initiation site is required for efficient proteasome-mediated degradation. Nat Struct Mol Biol 11(9):830–837. https://doi.org/10.1038/nsmb814
Romero P, Obradovic Z, Li X, Garner EC, Brown CJ, Dunker AK (2001) Sequence complexity of disordered protein. Proteins 42(1):38–48
Rubel MS, Fedotov SA, Grizel AV, Sopova JV, Malikova OA, Chernoff YO, Rubel AA (2020) Functional Mammalian Amyloids and Amyloid-Like Proteins. Life (Basel) 10(9):156. https://doi.org/10.3390/life10090156
Schad E, Tompa P, Hegyi H (2011) The relationship between proteome size, structural disorder and organism complexity. Genome Biol 12(12):R120. https://doi.org/10.1186/gb-2011-12-12-r120
Sergeeva AV, Galkin AP (2020) Functional amyloids of eukaryotes: criteria, classification, and biological significance. Curr Genet 66(5):849–866. https://doi.org/10.1007/s00294-020-01079-7
Sharma R, Raduly Z, Miskei M, Fuxreiter M (2015) Fuzzy complexes: Specific binding without complete folding. FEBS Lett 589(19 Pt A):2533–2542. https://doi.org/10.1016/j.febslet.2015.07.022
Singh GP, Ganapathi M, Sandhu KS, Dash D (2006) Intrinsic unstructuredness and abundance of PEST motifs in eukaryotic proteomes. Proteins 62(2):309–315. https://doi.org/10.1002/prot.20746
Tompa P (2011) Unstructural biology coming of age. Curr Opin Struct Biol 21(3):419–425. https://doi.org/10.1016/j.sbi.2011.03.012
Tompa P (2012) Intrinsically disordered proteins: a 10-year recap. Trends Biochem Sci 37(12):509–516. https://doi.org/10.1016/j.tibs.2012.08.004
Tompa P, Csermely P (2004) The role of structural disorder in the function of RNA and protein chaperones. FASEB J 18(11):1169–1175. https://doi.org/10.1096/fj.04-1584rev
Tompa P, Fuxreiter M (2008) Fuzzy complexes: polymorphism and structural disorder in protein-protein interactions. Trends Biochem Sci 33(1):2–8. https://doi.org/10.1016/j.tibs.2007.10.003
Tompa P, Kovacs D (2010) Intrinsically disordered chaperones in plants and animals. Biochem Cell Biol 88(2):167–174. https://doi.org/10.1139/o09-163
Tsvetkov P, Reuven N, Shaul Y (2009) The nanny model for IDPs. Nat Chem Biol 5(11):778–781. https://doi.org/10.1038/nchembio.233
Turoverov KK, Kuznetsova IM, Uversky VN (2010) The protein kingdom extended: ordered and intrinsically disordered proteins, their folding, supramolecular complex formation, and aggregation. Prog Biophys Mol Biol 102(2–3):73–84. https://doi.org/10.1016/j.pbiomolbio.2010.01.003
Uversky AV, Uversky VN (2014) Amino acid code for protein folding, misfolding, and non-folding. In: Farkas E, Ryadnov M (eds) Amino acids, peptides, and proteins, vol 39. RCS Publishing, London, pp 192–236. https://doi.org/10.1039/9781849739962-00192
Uversky VN (2002a) Natively unfolded proteins: a point where biology waits for physics. Protein Sci 11(4):739–756. https://doi.org/10.1110/ps.4210102
Uversky VN (2002b) What does it mean to be natively unfolded? Eur J Biochem 269(1):2–12. https://doi.org/10.1046/j.0014-2956.2001.02649.x
Uversky VN (2003) Protein folding revisited. A polypeptide chain at the folding-misfolding-nonfolding cross-roads: which way to go? Cell Mol Life Sci 60(9):1852–1871. https://doi.org/10.1007/s00018-003-3096-6
Uversky VN (2011a) Flexible nets of malleable guardians: intrinsically disordered chaperones in neurodegenerative diseases. Chem Rev 111(2):1134–1166. https://doi.org/10.1021/cr100186d
Uversky VN (2011b) Multitude of binding modes attainable by intrinsically disordered proteins: a portrait gallery of disorder-based complexes. Chem Soc Rev 40(3):1623–1634. https://doi.org/10.1039/c0cs00057d
Uversky VN (2013a) A decade and a half of protein intrinsic disorder: biology still waits for physics. Protein Sci 22(6):693–724. https://doi.org/10.1002/pro.2261
Uversky VN (2013b) Disorder in the lifetime of a protein. Intrinsically Disord Proteins 1(1):e26782. https://doi.org/10.4161/idp.26782
Uversky VN (2013c) Intrinsic disorder-based protein interactions and their modulators. Curr Pharm Des 19(23):4191–4213. https://doi.org/10.2174/1381612811319230005
Uversky VN (2013d) Under-folded proteins: Conformational ensembles and their roles in protein folding, function and pathogenesis. Biopolymers. https://doi.org/10.1002/bip.22298
Uversky VN (2013e) Unusual biophysics of intrinsically disordered proteins. Biochim Biophys Acta 1834(5):932–951. https://doi.org/10.1016/j.bbapap.2012.12.008
Uversky VN (2015) Functional roles of transiently and intrinsically disordered regions within proteins. FEBS J 282(7):1182–1189. https://doi.org/10.1111/febs.13202
Uversky VN (2016a) Dancing Protein Clouds: The Strange Biology and Chaotic Physics of Intrinsically Disordered Proteins. J Biol Chem 291(13):6681–6688. https://doi.org/10.1074/jbc.R115.685859
Uversky VN (2016b) p53 proteoforms and intrinsic disorder: an illustration of the protein structure-function continuum concept. Int J Mol Sci 17(11):1874. https://doi.org/10.3390/ijms17111874
Uversky VN (2016c) Paradoxes and wonders of intrinsic disorder: complexity of simplicity. Intrinsically Disord Proteins 4(1):e1135015. https://doi.org/10.1080/21690707.2015.1135015
Uversky VN (2019a) Intrinsically disordered proteins and their “mysterious” (meta)physics. Front Phys 7:Article 10 (18 pages). https://doi.org/10.3389/fphy.2019.00010
Uversky VN (2019b) Protein intrinsic disorder and structure-function continuum. Prog Mol Biol Transl Sci 166:1–17. https://doi.org/10.1016/bs.pmbts.2019.05.003
Uversky VN, Dunker AK (2010) Understanding protein non-folding. BBA-Proteins Proteom 1804(6):1231–1264. https://doi.org/10.1016/j.bbapap.2010.01.017
Uversky VN, Fink AL (2004) Conformational constraints for amyloid fibrillation: the importance of being unfolded. Biochim Biophys Acta 1698(2):131–153. https://doi.org/10.1016/j.bbapap.2003.12.008
Uversky VN, Gillespie JR, Fink AL (2000) Why are “natively unfolded” proteins unstructured under physiologic conditions? Proteins 41(3):415–427. https://doi.org/10.1002/1097-0134(20001115)41:3%3c415::AID-PROT130%3e3.0.CO;2-7
Uversky VN, Oldfield CJ, Dunker AK (2005) Showing your ID: intrinsic disorder as an ID for recognition, regulation and cell signaling. J Mol Recognit 18(5):343–384. https://doi.org/10.1002/jmr.747
Uversky VN, Oldfield CJ, Dunker AK (2008) Intrinsically disordered proteins in human diseases: introducing the D2 concept. Annu Rev Biophys 37:215–246. https://doi.org/10.1146/annurev.biophys.37.032807.125924
Vacic V, Oldfield CJ, Mohan A, Radivojac P, Cortese MS, Uversky VN, Dunker AK (2007) Characterization of molecular recognition features, MoRFs, and their binding partners. J Proteome Res 6(6):2351–2366. https://doi.org/10.1021/pr0701411
van der Lee R, Buljan M, Lang B, Weatheritt RJ, Daughdrill GW, Dunker AK, Fuxreiter M, Gough J, Gsponer J, Jones DT, Kim PM, Kriwacki RW, Oldfield CJ, Pappu RV, Tompa P, Uversky VN, Wright PE, Babu MM (2014) Classification of intrinsically disordered regions and proteins. Chem Rev 114(13):6589–6631. https://doi.org/10.1021/cr400525m
Van Melderen L, Thi MH, Lecchi P, Gottesman S, Couturier M, Maurizi MR (1996) ATP-dependent degradation of CcdA by Lon protease. Effects of secondary structure and heterologous subunit interactions. J Biol Chem 271(44):27730–27738. https://doi.org/10.1074/jbc.271.44.27730
Ward JJ, Sodhi JS, McGuffin LJ, Buxton BF, Jones DT (2004) Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. J Mol Biol 337(3):635–645. https://doi.org/10.1016/j.jmb.2004.02.002
Weber-Ban EU, Reid BG, Miranker AD, Horwich AL (1999) Global unfolding of a substrate protein by the Hsp100 chaperone ClpA. Nature 401(6748):90–93. https://doi.org/10.1038/43481
Wilson DN, Nierhaus KH (2005) Ribosomal proteins in the spotlight. Crit Rev Biochem Mol Biol 40(5):243–267. https://doi.org/10.1080/10409230500256523
Wright PE, Dyson HJ (1999) Intrinsically unstructured proteins: re-assessing the protein structure-function paradigm. J Mol Biol 293(2):321–331. https://doi.org/10.1006/jmbi.1999.3110
Wu Z, Hu G, Yang J, Peng Z, Uversky VN, Kurgan L (2015) In various protein complexes, disordered protomers have large per-residue surface areas and area of protein-. DNA- and RNA-binding interfaces. FEBS Lett 589(19 Pt A):2561–2569. https://doi.org/10.1016/j.febslet.2015.08.014
Xue B, Dunbrack RL, Williams RW, Dunker AK, Uversky VN (2010) PONDR-FIT: a meta-predictor of intrinsically disordered amino acids. Biochim Biophys Acta 1804(4):996–1010. https://doi.org/10.1016/j.bbapap.2010.01.011
Xue B, Dunker AK, Uversky VN (2012) Orderly order in protein intrinsic disorder distribution: disorder in 3500 proteomes from viruses and the three domains of life. J Biomol Struct Dyn 30(2):137–149. https://doi.org/10.1080/07391102.2012.675145
Zhou J, Oldfield CJ, Yan W, Shen B, Dunker AK (2020) Identification of Intrinsic Disorder in Complexes from the Protein Data Bank. ACS Omega 5(29):17883–17891. https://doi.org/10.1021/acsomega.9b03927
Funding
None
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares no competing interests.
Ethical approval
Not applicable
Additional information
Publisher's note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Uversky, V.N. The protein disorder cycle. Biophys Rev 13, 1155–1162 (2021). https://doi.org/10.1007/s12551-021-00853-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12551-021-00853-2