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Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small [[radius of gyration]]. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or [[hydrodynamic drag]], such as [[size exclusion chromatography]], [[analytical ultracentrifugation]], [[Small angle X-ray scattering (SAXS)]], and measurements of the [[diffusion constant]]. Unfolded proteins are also characterized by their lack of [[secondary structure]], as assessed by far-UV (170-250&nbsp;nm) [[circular dichroism]] (esp. a pronounced minimum at ~200&nbsp;nm) or [[infrared]] spectroscopy. Unfolded proteins also have exposed backbone [[peptide]] groups exposed to solvent, so that they are readily cleaved by [[protease]]s, undergo rapid [[hydrogen-deuterium exchange]] and exhibit a small dispersion (<1 ppm) in their 1H amide [[chemical shift]]s as measured by [[protein NMR|NMR]]. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.)
Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small [[radius of gyration]]. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or [[hydrodynamic drag]], such as [[size exclusion chromatography]], [[analytical ultracentrifugation]], [[Small angle X-ray scattering (SAXS)]], and measurements of the [[diffusion constant]]. Unfolded proteins are also characterized by their lack of [[secondary structure]], as assessed by far-UV (170-250&nbsp;nm) [[circular dichroism]] (esp. a pronounced minimum at ~200&nbsp;nm) or [[infrared]] spectroscopy. Unfolded proteins also have exposed backbone [[peptide]] groups exposed to solvent, so that they are readily cleaved by [[protease]]s, undergo rapid [[hydrogen-deuterium exchange]] and exhibit a small dispersion (<1 ppm) in their 1H amide [[chemical shift]]s as measured by [[protein NMR|NMR]]. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.)
Recently, new methods including [[Fast parallel proteolysis (FASTpp)]] have been introduced, which allow to determine the fraction folded/disordered without the need for purification.<ref name="fastpp">{{Cite journal |doi=10.1371/journal.pone.0046147 |title=Determining Biophysical Protein Stability in Lysates by a Fast Proteolysis Assay, FASTpp |year=2012 |editor1-last=Uversky |editor1-first=Vladimir N |last1=Minde |first1=David P. |last2=Maurice |first2=Madelon M. |last3=Rüdiger |first3=Stefan G. D. |journal=PLoS ONE |volume=7 |issue=10 |pages=e46147 |pmid=23056252 |pmc=3463568}}</ref><ref name="methods">{{cite journal |pmid=15782190 |year=2005 |last1=Park |first1=C |last2=Marqusee |first2=S |title=Pulse proteolysis: A simple method for quantitative determination of protein stability and ligand binding |volume=2 |issue=3 |pages=207–12 |doi=10.1038/nmeth740 |journal=Nature Methods}}</ref> Even subtle differences in the stability of missense mutations, protein partner binding and (self)polymerisation-induced folding of (e.g.) coiled-coils can be detected using FASTpp as recently demonstrated using the tropomyosin-troponin protein interaction.<ref name="Robaszkiewicz2015">{{Cite journal | doi = 10.1016/j.bbapap.2015.01.004| title = Impaired tropomyosin–troponin interactions reduce activation of the actin thin filament| journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics| year = 2015| last1 = Robaszkiewicz | first1 = K. | last2 = Ostrowska | first2 = Z. | last3 = Cyranka-Czaja | first3 = A. | last4 = Moraczewska | first4 = J. | volume=1854 | pages=381–390}}</ref>
Recently, new methods including [[Fast parallel proteolysis (FASTpp)]] have been introduced, which allow to determine the fraction folded/disordered without the need for purification.<ref name="fastpp">{{Cite journal |doi=10.1371/journal.pone.0046147 |title=Determining Biophysical Protein Stability in Lysates by a Fast Proteolysis Assay, FASTpp |year=2012 |editor1-last=Uversky |editor1-first=Vladimir N |last1=Minde |first1=David P. |last2=Maurice |first2=Madelon M. |last3=Rüdiger |first3=Stefan G. D. |journal=PLoS ONE |volume=7 |issue=10 |pages=e46147 |pmid=23056252 |pmc=3463568}}</ref><ref name="methods">{{cite journal |pmid=15782190 |year=2005 |last1=Park |first1=C |last2=Marqusee |first2=S |title=Pulse proteolysis: A simple method for quantitative determination of protein stability and ligand binding |volume=2 |issue=3 |pages=207–12 |doi=10.1038/nmeth740 |journal=Nature Methods}}</ref> Even subtle differences in the stability of missense mutations, protein partner binding and (self)polymerisation-induced folding of (e.g.) coiled-coils can be detected using FASTpp as recently demonstrated using the tropomyosin-troponin protein interaction.<ref name="Robaszkiewicz2015">{{Cite journal | doi = 10.1016/j.bbapap.2015.01.004| title = Impaired tropomyosin–troponin interactions reduce activation of the actin thin filament| journal = Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics| year = 2015| last1 = Robaszkiewicz | first1 = K. | last2 = Ostrowska | first2 = Z. | last3 = Cyranka-Czaja | first3 = A. | last4 = Moraczewska | first4 = J. | volume=1854 | pages=381–390}}</ref> Fully unstructured protein regions can be experimentally validated by their hypersusceptibility to proteolysis using short digestion times and low protease concentrations. <ref name="APC-Axin-proteolysis">{{Cite journal |doi= 10.1371/journal.pone.0077257|title= Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations |year=2013 |editor1-last=Buckle |editor1-first=Ashley M |last1=Minde |first1=David P.|last2=Radli |first2=Martina |last3=Forneris |first3=Frederico|last4=Maurice |first4=Madelon M. |last5=Rüdiger |first5=Stefan G. D. |journal=PLoS ONE |volume=8 |issue=10 |pages=e77257 |pmid=24130866 |pmc=PMC3793970}}</ref>


Bulk methods to study IDP structure and dynamics include [[SAXS]] for ensemble shape information, [[NMR]] for atomistic ensemble refinement, [[Fluorescence]] for visualising molecular interactions and conformational transitions, x-ray crystallography to highlight more mobile regions in otherwise rigid protein crystals, cryo-EM to reveal less fixed parts of proteins, light scattering to monitor size distributions of IDPs or their aggregation kinetics, [[Circular Dichroism]] to monitor secondary structure of IDPs.
Bulk methods to study IDP structure and dynamics include [[SAXS]] for ensemble shape information, [[NMR]] for atomistic ensemble refinement, [[Fluorescence]] for visualising molecular interactions and conformational transitions, x-ray crystallography to highlight more mobile regions in otherwise rigid protein crystals, cryo-EM to reveal less fixed parts of proteins, light scattering to monitor size distributions of IDPs or their aggregation kinetics, [[Circular Dichroism]] to monitor secondary structure of IDPs.

Version vom 29. April 2016, 14:38 Uhr

Conformational flexibility in SUMO-1 protein (PDB:1a5r). The central part shows relatively ordered structure. Conversely, the N- and C-terminal regions (left and right, respectively) show ‘intrinsic disorder’, although a short helical region persists in the N-terminal tail. Ten alternative NMR models were morphed. Secondary structure elements: α-helices (red), β-strands (blue arrows). [1]

An intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure.[2][3][4] IDPs cover a spectrum of states from fully unstructured to partially structured and include random coils, (pre-)molten globules, and large multi-domain proteins connected by flexible linkers. They constitute one of the main types of protein (alongside globular, fibrous and membrane proteins).[5]

The discovery of IDPs has challenged the traditional protein structure paradigm, that protein function depends on a fixed three-dimensional structure. This dogma has been challenged over the last decades by increasing evidence from various branches of structural biology, suggesting that protein dynamics may be highly relevant for such systems. Despite their lack of stable structure, IDPs are a very large and functionally important class of proteins. In some cases, IDPs can adopt a fixed three-dimensional structure after binding to other macromolecules. Overall, IDPs are different from structured proteins in many ways and tend to have distinct properties in terms of function, structure, sequence, interactions, evolution and regulation.[6]

History

An ensemble of NMR structures of the Thylakoid soluble phosphoprotein TSP9, which shows a largely flexible protein chain.[7]

In the 1930s -1950s, the first protein structures were solved by protein crystallography. These early structures suggested that a fixed three-dimensional structure might be generally required to mediate biological functions of proteins. In the 1960s, Levinthal's paradox suggested that the systematic conformational search of a long polypeptide is unlikely to yield a single folded protein structure on biologically relevant timescales (i.e. seconds to minutes). Curiously, for many (small) proteins or protein domains, relatively rapid and efficient refolding can be observed in vitro. As stated in Anfinsen's Dogma from 1973, the fixed 3D structure of these proteins is uniquely encoded in its primary structure (the amino acid sequence), is kinetically accessible and stable under a range of (near) physiological conditions, and can therefore be considered as the native state of such "ordered" proteins.Vorlage:Citation needed

During the subsequent decades, however, many large protein regions could not be assigned in x-ray datasets, indicating that they occupy multiple positions which average out in electron density maps. The lack of a fixed, unique positions relative to the crystal lattice suggested that these regions were "disordered". Additional techniques for determining protein structures, such as NMR, demonstrated the presence of large flexible linkers and termini in many solved structural ensembles. It is now generally accepted that proteins exist as an ensemble of similar structures with some regions more constrained than others. Intrinsically Unstructured Proteins (IUPs) occupy the extreme end of this spectrum of flexibility, whereas IDPs also include proteins of considerable local structure tendency or flexible multidomain assemblies.These highly dynamic disordered regions of proteins have subsequently been linked to functionally important phenomena such as allosteric regulation and enzyme catalysis. [8] [9]

In the 2000s, bioinformatic predictions of intrinsic disorder in proteins indicated that intrinsic disorder is more common in sequenced/predicted proteomes than in known structures in the protein database. Based on DISOPRED2 prediction, long (>30 residue) disordered segments occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins.[10]

In the 2010s it became clear that IDPs are highly abundant among disease-related proteins.[11]

Biological roles

Many disordered proteins have the binding affinity with their receptors regulated by post-translational modification, thus it has been proposed that the flexibility of disordered proteins facilitates the different conformational requirements for binding the modifying enzymes as well as their receptors.[12] Intrinsic disorder is particularly enriched in proteins implicated in cell signaling, transcription and chromatin remodeling functions.[13][14]

Flexible linkers

Disordered regions are often found as flexible linkers (or loops) connecting two globular or transmembrane domains. Linker sequences vary greatly in length and amino acid sequence, but are similar in amino acid composition (rich in polar uncharged amino acids). Flexible linkers allow the connecting domains to freely twist and rotate through space to recruit their binding partners or for those binding partners to induce larger scale interdomain conformation changes via protein domain dynamics.

Linear motifs

Linear motifs are short disordered segments of proteins that mediate functional interactions with other proteins or other biomolecules (RNA, DNA, sugars etc.). Many roles or linear motifs are associated with cell regulation, for instance in control of cell shape, subcellular localisation of individual proteins and regulated protein turnover. Often, post-translational modifications such as phosphorylation tune the affinity (not rarely by several orders of magnitude) of individual linear motifs for specific interactions. Relatively rapid evolution and a relatively small number of structural restraints for establishing novel (low-affinity) interfaces make it particularly challenging to detect linear motifs but their widespread biological roles and the fact that many viruses mimick/hijack linear motifs to efficiently recode infected cells underlines the timely urgency of research on this very challenging and exciting topic. Unlike globular proteins IDPs do not have spatially-disposed active pockets. Nevertheless, in 80% of IDPs (~3 dozens) subjected to detailed structural chacterization by NMR there are linear motifs termed PreSMos (pre-structured motifs) that are transient secondary structural elements primed for target recognition. In several cases it has been demonstrated that these transient structures become full and stable secondary structures, e.g., helices, upon target binding. Hence, PreSMos are the putative active sites in IDPs.[15]

Coupled folding and binding

Many unstructured proteins undergo transitions to more ordered states upon binding to their targets (e.g. Molecular Recognition Features (MoRFs)[16]). The coupled folding and binding may be local, involving only a few interacting residues, or it might involve an entire protein domain. It was recently shown that the coupled folding and binding allows the burial of a large surface area that would be possible only for fully structured proteins if they were much larger.[17] Moreover, certain disordered regions might serve as "molecular switches" in regulating certain biological function by switching to ordered conformation upon molecular recognition like small molecule-binding, DNA/RNA binding, ion interactions etc.[18]

The ability of disordered proteins to bind, and thus to exert a function, shows that stability is not a required condition. Many short functional sites, for example Short Linear Motifs are over-represented in disordered proteins.

Disorder in the bound state (fuzzy complexes)

Intrinsically disordered proteins can retain their conformational freedom even when they bind specifically to other proteins. The structural disorder in bound state can be static or dynamic. In fuzzy complexes structural multiplicity is required for function and the manipulation of the bound disordered region changes activity. The conformational ensemble of the complex is modulated via post-translational modifications or protein interactions.[19] Specificity of DNA binding proteins often depends on the length of fuzzy regions, which is varied by alternative splicing.[20]

Disorder identification and analysis

Disorder prediction software

REMARK465 - missing electron densities in X-ray structure representing protein disorder (PDB 1a22, human growth hormone bound to receptor). Compilation of screenshots from PDB database and molecule representation via VMD. Blue and red arrows point to missing residues on receptor and growth hormone, respectively.


Disorder prediction algorithms can predict Intrinsic Disorder (ID) propensity with high accuracy (approaching around 80%) based on primary sequence composition, similarity to unassigned segments in protein x-ray datasets, flexible regions in NMR studies and physico-chemical properties of amino acids.

Intrinsically unstructured proteins are characterized by a low content of bulky hydrophobic amino acids and a high proportion of polar and charged amino acids. Thus disordered sequences cannot bury sufficient hydrophobic core to fold like stable globular proteins. In some cases, hydrophobic clusters in disordered sequences provide the clues for identifying the regions that undergo coupled folding and binding. Such signatures are the basis of the prediction methods below.

Many disordered proteins also reveal low complexity sequences, i.e. sequences with over-representation of a few residues. While low complexity sequences are a strong indication of disorder, the reverse is not necessarily true, that is, not all disordered proteins have low complexity sequences. Disordered proteins have a low content of predicted secondary structure. There are many computational methods that exploit sequence information to predict whether a protein is disordered.[21] Notable examples of such software include IUPRED and Disopred. Different software may use different definitions of disorder. Since the methods above use different definitions of disorder and they were trained on different datasets, it is difficult to estimate their relative accuracy. Disorder prediction category is a part of biannual CASP experiment that is designed to test methods according accuracy in finding regions with missing 3D structure (marked in PDB files as REMARK465, missing electron densities in X-ray structures).

Experimental validation

Intrinsically unfolded proteins, once purified, can be identified by various experimental methods. The primary method to obtain information on disordered regions of a protein is NMR spectroscopy. The lack of electron density in X-ray crystallographic studies may also be a sign of disorder.

Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small radius of gyration. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or hydrodynamic drag, such as size exclusion chromatography, analytical ultracentrifugation, Small angle X-ray scattering (SAXS), and measurements of the diffusion constant. Unfolded proteins are also characterized by their lack of secondary structure, as assessed by far-UV (170-250 nm) circular dichroism (esp. a pronounced minimum at ~200 nm) or infrared spectroscopy. Unfolded proteins also have exposed backbone peptide groups exposed to solvent, so that they are readily cleaved by proteases, undergo rapid hydrogen-deuterium exchange and exhibit a small dispersion (<1 ppm) in their 1H amide chemical shifts as measured by NMR. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.) Recently, new methods including Fast parallel proteolysis (FASTpp) have been introduced, which allow to determine the fraction folded/disordered without the need for purification.[22][23] Even subtle differences in the stability of missense mutations, protein partner binding and (self)polymerisation-induced folding of (e.g.) coiled-coils can be detected using FASTpp as recently demonstrated using the tropomyosin-troponin protein interaction.[24] Fully unstructured protein regions can be experimentally validated by their hypersusceptibility to proteolysis using short digestion times and low protease concentrations. [25]

Bulk methods to study IDP structure and dynamics include SAXS for ensemble shape information, NMR for atomistic ensemble refinement, Fluorescence for visualising molecular interactions and conformational transitions, x-ray crystallography to highlight more mobile regions in otherwise rigid protein crystals, cryo-EM to reveal less fixed parts of proteins, light scattering to monitor size distributions of IDPs or their aggregation kinetics, Circular Dichroism to monitor secondary structure of IDPs.

Single-molecule methods to study IDPs include spFRET[26] to study conformational flexibility of IDPs and the kinetics of structural transitions, optical tweezers[27] for high-resolution insights into the ensembles of IDPs and their oligomers or aggregates, nanopores[28] to reveal global shape distributions of IDPs, magnetic tweezers[29] to study structural transitions for long times at low forces, high-speed AFM[30] to visualise the spatio-temporal flexibility of IDPs directly.

Disorder and disease

Intrinsically unstructured proteins have been implicated in a number of diseases.[31] Aggregation of misfolded proteins is the cause of many synucleinopathies. The aggregation of the intrinsically unstructured protein α-Synuclein is thought to be responsible. The structural flexibility of this protein together with its susceptibility to modification in the cell leads to misfolding and aggregation. Genetics, oxidative and nitrative stress as well as mitochondrial impairment impact the structural flexibility of the unstructured α-Synuclein protein and associated disease mechanisms.[32] Many key oncogenes have large intrinsically unstructured regions, for example p53 and BRCA1. These regions of the proteins are responsible for mediating many of their interactions.

Computer simulations

Structural and dynamical properties of intrinsically unstructured proteins are being studied by molecular dynamics simulations.[33][34][35] Findings from these simulations suggest a highly flexible conformational ensemble of intrinsically disordered proteins at different temperatures which is related to the presence of low free energy barriers.

Effects of confinement have also recently been addressed.[36] For example, these studies suggest that confinement tends to increase the population of turn structures with respect to the population of coils and β-hairpins.

Moreover, various protocols and methods of analyzing IDPs, such as studies based on quantitative analysis of GC content in genes and their respective chromosomal bands, have been used to understand functional IDP segments.[37][38]

Pioneering IDP research labs

In the last ten years, a great number of laboratories have investigated protein disorders using both experimental (e.g. SAXS-NMR, single-molecule fluorescence) and computational (analysis of protein structure) techniques.

See also

References

Vorlage:Reflist[39]

  1. ↑ J Bujnicki (Hrsg.): Prediction of Protein Structures, Functions, and Interactions. John Wiley & Sons, Ltd., 2008, ISBN 978-0-470-51767-3, Chapter 2: First Steps of Protein Structure Prediction, S. 39–62, doi:10.1002/9780470741894.ch2 (genesilico.pl [PDF]).
  2. ↑ A. K. Dunker, J. D. Lawson, C. J. Brown, R. M. Williams, P Romero, J. S. Oh, C. J. Oldfield, A. M. Campen, C. M. Ratliff, K. W. Hipps, J Ausio, M. S. Nissen, R Reeves, C Kang, C. R. Kissinger, R. W. Bailey, M. D. Griswold, W Chiu, E. C. Garner, Z Obradovic: Intrinsically disordered protein. In: Journal of molecular graphics & modelling. 19. Jahrgang, Nr. 1, 2001, S. 26–59, doi:10.1016/s1093-3263(00)00138-8, PMID 11381529.
  3. ↑ Dyson HJ, Wright PE: Intrinsically unstructured proteins and their functions. In: Nat. Rev. Mol. Cell Biol. 6. Jahrgang, Nr. 3, März 2005, S. 197–208, doi:10.1038/nrm1589, PMID 15738986.
  4. ↑ Dunker AK, Silman I, Uversky VN, Sussman JL: Function and structure of inherently disordered proteins. In: Curr. Opin. Struct. Biol. 18. Jahrgang, Nr. 6, Dezember 2008, S. 756–64, doi:10.1016/j.sbi.2008.10.002, PMID 18952168.
  5. ↑ A Andreeva: SCOP2 prototype: a new approach to protein structure mining. In: Nucleic Acids Res. 42. Jahrgang, 2014, S. D310–4, doi:10.1093/nar/gkt1242, PMID 24293656, PMC 3964979 (freier Volltext).
  6. ↑ Robin van der Lee, Marija Buljan, Benjamin Lang, Robert J. Weatheritt, Gary W. Daughdrill, A. Keith Dunker, Monika Fuxreiter, Julian Gough: Classification of Intrinsically Disordered Regions and Proteins. In: Chemical Reviews. 114. Jahrgang, Nr. 13, 9. Juli 2014, ISSN 0009-2665, S. 6589–6631, doi:10.1021/cr400525m, PMID 24773235, PMC 4095912 (freier Volltext) – (doi.org).
  7. ↑ Song J, Lee MS, Carlberg I, Vener AV, Markley JL: Micelle-induced folding of spinach thylakoid soluble phosphoprotein of 9 kDa and its functional implications. In: Biochemistry. 45. Jahrgang, Nr. 51, Dezember 2006, S. 15633–43, doi:10.1021/bi062148m, PMID 17176085, PMC 2533273 (freier Volltext).
  8. ↑ Bu Z, Callaway DJ: Proteins MOVE! Protein dynamics and long-range allostery in cell signaling. In: Adv in Protein Chemistry and Structural Biology (= Advances in Protein Chemistry and Structural Biology). 83. Jahrgang, 2011, S. 163–221, doi:10.1016/B978-0-12-381262-9.00005-7, PMID 21570668 (elsevier.com).
  9. ↑ S. C. Kamerlin, A Warshel: At the dawn of the 21st century: Is dynamics the missing link for understanding enzyme catalysis? In: Proteins: Structure, Function, and Bioinformatics. 78. Jahrgang, Nr. 6, 2010, S. 1339–75, doi:10.1002/prot.22654, PMID 20099310, PMC 2841229 (freier Volltext).
  10. ↑ J. J. Ward, J. S. Sodhi, L. J. McGuffin, B. F. Buxton, D. T. Jones: Prediction and functional analysis of native disorder in proteins from the three kingdoms of life. In: Journal of Molecular Biology. 337. Jahrgang, Nr. 3, 2004, S. 635–45, doi:10.1016/j.jmb.2004.02.002, PMID 15019783.
  11. ↑ V. N. Uversky, C. J. Oldfield, A. K. Dunker: Intrinsically Disordered Proteins in Human Diseases: Introducing the D2Concept. In: Annual Review of Biophysics. 37. Jahrgang, 2008, S. 215–246, doi:10.1146/annurev.biophys.37.032807.125924, PMID 18573080.
  12. ↑ Collins MO, Yu L, Campuzano I, Grant SG, Choudhary JS: Phosphoproteomic analysis of the mouse brain cytosol reveals a predominance of protein phosphorylation in regions of intrinsic sequence disorder. In: Mol. Cell Proteomics. 7. Jahrgang, Nr. 7, Juli 2008, S. 1331–48, doi:10.1074/mcp.M700564-MCP200, PMID 18388127.
  13. ↑ Iakoucheva LM, Brown CJ, Lawson JD, Obradović Z, Dunker AK: Intrinsic disorder in cell-signaling and cancer-associated proteins. In: J. Mol. Biol. 323. Jahrgang, Nr. 3, Oktober 2002, S. 573–84, doi:10.1016/S0022-2836(02)00969-5, PMID 12381310.
  14. ↑ Sandhu KS: Intrinsic disorder explains diverse nuclear roles of chromatin remodeling proteins. In: J. Mol. Recognit. 22. Jahrgang, Nr. 1, 2009, S. 1–8, doi:10.1002/jmr.915, PMID 18802931.
  15. ↑ Si-Hyung Lee, Do-Hyoung Kim, Joan J. Han, Eun-Ji Cha, Ji-Eun Lim, Ye-Jin Cho, Chewook Lee, Kyou-Hoon Han: Understanding Pre-Structured Motifs (PreSMos) in Intrinsically Unfolded Proteins. In: Current Protein & Peptide Science. 13. Jahrgang, Nr. 1, Februar 2012, S. 34–54, doi:10.2174/138920312799277974, PMID 22044148 (eurekaselect.com).
  16. ↑ Amrita Mohan, Christopher J. Oldfield, Predrag Radivojac, Vladimir Vacic, Marc S. Cortese, A. Keith Dunker, Vladimir N. Uversky: Analysis of Molecular Recognition Features (MoRFs). In: Journal of Molecular Biology 2006 Oct 6. 362(5). Jahrgang, S. 1043–59, doi:10.1016/j.jmb.2006.07.087, PMID 16935303 (sciencedirect.com).
  17. ↑ Gunasekaran K, Tsai CJ, Kumar S, Zanuy D, Nussinov R: Extended disordered proteins: targeting function with less scaffold. In: Trends Biochem. Sci. 28. Jahrgang, Nr. 2, Februar 2003, S. 81–5, doi:10.1016/S0968-0004(03)00003-3, PMID 12575995.
  18. ↑ Sandhu KS, Dash D: Dynamic alpha-helices: conformations that do not conform. In: Proteins. 68. Jahrgang, Nr. 1, Juli 2007, S. 109–22, doi:10.1002/prot.21328, PMID 17407165.
  19. ↑ M Fuxreiter: Fuzziness: Linking regulation to protein dynamics. In: Molecular bioSystems. 8. Jahrgang, Nr. 1, 2012, S. 168–77, doi:10.1039/c1mb05234a, PMID 21927770.
  20. ↑ M Fuxreiter, I Simon, S Bondos: Dynamic protein-DNA recognition: Beyond what can be seen. In: Trends in Biochemical Sciences. 36. Jahrgang, Nr. 8, 2011, S. 415–23, doi:10.1016/j.tibs.2011.04.006, PMID 21620710.
  21. ↑ Ferron F, Longhi S, Canard B, Karlin D: A practical overview of protein disorder prediction methods. In: Proteins. 65. Jahrgang, Nr. 1, Oktober 2006, S. 1–14, doi:10.1002/prot.21075, PMID 16856179.
  22. ↑ David P. Minde, Madelon M. Maurice, Stefan G. D. Rüdiger: Determining Biophysical Protein Stability in Lysates by a Fast Proteolysis Assay, FASTpp. In: PLoS ONE. 7. Jahrgang, Nr. 10, 2012, S. e46147, doi:10.1371/journal.pone.0046147, PMID 23056252, PMC 3463568 (freier Volltext).
  23. ↑ C Park, S Marqusee: Pulse proteolysis: A simple method for quantitative determination of protein stability and ligand binding. In: Nature Methods. 2. Jahrgang, Nr. 3, 2005, S. 207–12, doi:10.1038/nmeth740, PMID 15782190.
  24. ↑ K. Robaszkiewicz, Z. Ostrowska, A. Cyranka-Czaja, J. Moraczewska: Impaired tropomyosin–troponin interactions reduce activation of the actin thin filament. In: Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1854. Jahrgang, 2015, S. 381–390, doi:10.1016/j.bbapap.2015.01.004.
  25. ↑ David P. Minde, Martina Radli, Frederico Forneris, Madelon M. Maurice, Stefan G. D. Rüdiger: Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations. In: PLoS ONE. 8. Jahrgang, Nr. 10, 2013, S. e77257, doi:10.1371/journal.pone.0077257, PMID 24130866, PMC 3793970 (freier Volltext).
  26. ↑ M Brucale, B Schuler, B Samorì: Single-Molecule Studies of Intrinsically Disordered Proteins. In: Chemical Reviews. 114. Jahrgang, Nr. 6, 2014, S. 140117081415006, doi:10.1021/cr400297g, PMID 24432838.
  27. ↑ K Neupane, A Solanki, I Sosova, M Belov, M. T. Woodside: Diverse metastable structures formed by small oligomers of α-synuclein probed by force spectroscopy. In: PLoS ONE. 9. Jahrgang, Nr. 1, 2014, S. e86495, doi:10.1371/journal.pone.0086495, PMID 24475132, PMC 3901707 (freier Volltext).
  28. ↑ D Japrung, J Dogan, K. J. Freedman, A Nadzeyka, S Bauerdick, T Albrecht, M. J. Kim, P Jemth, J. B. Edel: Single-molecule studies of intrinsically disordered proteins using solid-state nanopores. In: Analytical Chemistry. 85. Jahrgang, Nr. 4, 2013, S. 2449–56, doi:10.1021/ac3035025, PMID 23327569.
  29. ↑ D Min, K Kim, C Hyeon, Y. H. Cho, Y. K. Shin, T. Y. Yoon: Mechanical unzipping and rezipping of a single SNARE complex reveals hysteresis as a force-generating mechanism. In: Nature Communications. 4. Jahrgang, Nr. 4, 2013, S. 1705, doi:10.1038/ncomms2692, PMID 23591872, PMC 3644077 (freier Volltext).
  30. ↑ A Miyagi, Y Tsunaka, T Uchihashi, K Mayanagi, S Hirose, K Morikawa, T Ando: Visualization of intrinsically disordered regions of proteins by high-speed atomic force microscopy. In: ChemPhysChem. 9. Jahrgang, Nr. 13, 2008, S. 1859–66, doi:10.1002/cphc.200800210, PMID 18698566.
  31. ↑ Vladimir N. Uversky, Christopher J. Oldfield, A. Keith Dunker: Intrinsically Disordered Proteins in Human Diseases: Introducing the D2Concept. In: Annual Review of Biophysics. 37. Jahrgang, 2008, S. 215–46, doi:10.1146/annurev.biophys.37.032807.125924, PMID 18573080.
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  33. ↑ Mittal J, Yoo T, Georgiou G, Truskett T: Structural Ensemble of an Intrinsically Disordered Polypeptide. In: J. Of Phys. Chem B. 117. Jahrgang, Dezember 2013, S. 118–124, doi:10.1021/jp308984e.
  34. ↑ Ojeda-May P, Pu J: Replica exchange molecular dynamics simulations of an α/β-type small acid soluble protein (SASP). In: Biophysical Chemistry. 184. Jahrgang, August 2013, S. 17–21, doi:10.1016/j.bpc.2013.07.014, PMID 24029407.
  35. ↑ Higo J, Ito H, Kuroda M, Ono S, Nakajima N, Nakamura H: Energy landscape of a peptide consisting of α-helix, 3-10-helix, β-hairpin, and other disordered conformations. In: Protein Science. 10. Jahrgang, Nr. 6, März 2001, S. 1160–1171, doi:10.1110/ps.44901, PMID 11369854, PMC 2374007 (freier Volltext).
  36. ↑ Rao J, Cruz L: Effects of Confinement on the Structure and Dynamics of an Intrinsically Disordered Peptide: A Molecular-Dynamics Study. In: J. Of Phys. Chem B. 117. Jahrgang, Nr. 14, März 2013, S. 3707–3719, doi:10.1021/jp310623x.
  37. ↑ Vladimir N Uversky: Digested disorder: Quarterly intrinsic disorder digest (January/February/March, 2013). In: Intrinsically Disordered Proteins. 1. Jahrgang, 2013, S. e25496, doi:10.4161/idp.25496.
  38. ↑ Susan Costantini, Ankush Sharma, Raffaele Raucci, Maria Costantini, Ida Autiero, and Giovanni Colonna: Genealogy of an ancient protein family: the Sirtuins, a family of disordered members. In: BMC Evolutionary Biology. 13. Jahrgang, März 2013, S. 60, doi:10.1186/1471-2148-13-60, PMID 23497088, PMC 3599600 (freier Volltext).
  39. ↑ Understanding Pre-Structured Motifs (PreSMos) in Intrinsically Unfolded Proteins. In: Curr Protein Pept Sci 13(1) 34-54. 13. Jahrgang, Februar 2012, S. 34–54, doi:10.2174/138920312799277974, PMID 22044148.
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