The unfoldomics decade: an update on intrinsically disordered proteins

Dunker, A. Keith; Oldfield, Christopher J.; Meng, Jingwei; Romero, Pedro; Yang, Jack; Chen, Jessica Walton; Vacic, Vladimir; Obradović, Zoran; Uversky, Vladimir N.

doi:10.1186/1471-2164-9-s2-s1

Cited by 486 publications

(450 citation statements)

References 165 publications

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“…The protein was then phosphorylated, or dialyzed, against NMR buffer consisting of 50 mM MOPS, pH 6.9, 150 mM NaCl, and 0.7 mM TCEP. MAP2c was expressed in M9 medium containing 15 N NH 4 Cl and/or 13 C glucose for NMR measurement.…”

Section: Preparation Of Recombinant Proteinsmentioning

confidence: 99%

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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Edited by Norma AllewellMicrotubule-associated protein 2c (MAP2c) is involved in neuronal development and is less characterized than its homolog Tau, which has various roles in neurodegeneration. Using NMR methods providing single-residue resolution and quantitative comparison, we investigated molecular interactions important for the regulatory roles of MAP2c in microtubule dynamics. We found that MAP2c and Tau significantly differ in the position and kinetics of sites that are phosphorylated by cAMP-dependent protein kinase (PKA), even in highly homologous regions. We determined the binding sites of unphosphorylated and phosphorylated MAP2c responsible for interactions with the regulatory protein 14-3-3 . Differences in phosphorylation and in charge distribution between MAP2c and Tau suggested that both MAP2c and Tau respond to the same signal (phosphorylation by PKA) but have different downstream effects, indicating a signaling branch point for controlling microtubule stability. Although the interactions of phosphorylated Tau with 14-3-3 are supposed to be a major factor in microtubule destabilization, the binding of 14-3-3 to MAP2c enhanced by PKA-mediated phosphorylation is likely to influence microtubule-MAP2c binding much less, in agreement with the results of our tubulin co-sedimentation measurements. The specific location of the major MAP2c phosphorylation site in a region homologous to the muscarinic receptor-binding site of Tau suggests that MAP2c also may regulate processes other than microtubule dynamics.Cytoskeletal microtubule-associated proteins (MAPs) 3 are proteins of critical importance for regulating the stability and dynamics of microtubules (1). MAP2 and Tau represent MAP subfamilies expressed in neurons; MAP2 is localized in dendrites, whereas Tau is found mainly in axons (2). Tau and MAP2 belong to the class of intrinsically disordered proteins (IDPs), which lack a unique structure and which exist in multiple, quickly interconverting conformations (3-7). NMR is the method of choice for structural investigation of this type of protein. Tau and MAP2 differ in their N-terminal projection domains, which contain acidic and proline-rich subdomains, whereas the C-terminal parts, containing the microtubulebinding domain (MTBD) and the C-terminal region, are homologous (8). Tau is expressed in several splice variants. The human brain isoforms differ in the number of microtubulebinding regions (MTBRs) in the C-terminal portion and in the presence of two inserts near the N terminus. For the sake of simplicity, only the 441-residue variant lacking exons 6, 8, and 10 (9) is discussed in this paper. This variant has been studied in detail and was shown to form paired helical filaments and neurofibillary tangles in brains of patients suffering from Alzheimer's disease (10). The MAP2 family is composed of two high-molecular-weight proteins, MAP2a and MAP2b, each consisting of 1830 amino acids, and two low-molecular-weight proteins, MAP2c and MAP2d, consisting of 467 and 498 amino acids, respectively. The ...

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Section: Preparation Of Recombinant Proteinsmentioning

confidence: 99%

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Jansen

Melková

Trošanová

et al. 2017

Journal of Biological Chemistry

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“…The one exception to this general trend is Leu, which has neutral propensity for very high S 2 RCI values 40.9 and is less indisposed towards adopting highly dynamic states; this might indicate it is typically more involved in dynamic processes. The amino acids in this group exactly match prior knowledge about order-promoting amino acids [23][24][25] , which is related to hydrophobicity as was already established in the context of protein disorder 26,27 but are here quantified according to their backbone dynamics behaviour in proteins.…”

Section: Resultsmentioning

confidence: 99%

From protein sequence to dynamics and disorder with DynaMine

et al. 2013

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Protein function and dynamics are closely related; however, accurate dynamics information is difficult to obtain. Here based on a carefully assembled data set derived from experimental data for proteins in solution, we quantify backbone dynamics properties on the amino-acid level and develop DynaMine-a fast, high-quality predictor of protein backbone dynamics. DynaMine uses only protein sequence information as input and shows great potential in distinguishing regions of different structural organization, such as folded domains, disordered linkers, molten globules and pre-structured binding motifs of different sizes. It also identifies disordered regions within proteins with an accuracy comparable to the most sophisticated existing predictors, without depending on prior disorder knowledge or three-dimensional structural information. DynaMine provides molecular biologists with an important new method that grasps the dynamical characteristics of any protein of interest, as we show here for human p53 and E1A from human adenovirus 5.

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“…It may be an interesting case to study intrinsically disordered proteins (29), but, for folded proteins, considering δz > 0 is more realistic. Henceforth we focus on that case and choose z = 5.…”

Section: Architecture Of Allosteric Networkmentioning

confidence: 99%

Architecture and coevolution of allosteric materials

Yan

Ravasio

Brito

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

120

138

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We introduce a numerical scheme to evolve functional elastic materials that can accomplish a specified mechanical task. In this scheme, the number of solutions, their spatial architectures, and the correlations among them can be computed. As an example, we consider an "allosteric" task, which requires the material to respond specifically to a stimulus at a distant active site. We find that functioning materials evolve a less-constrained trumpetshaped region connecting the stimulus and active sites, and that the amplitude of the elastic response varies nonmonotonically along the trumpet. As previously shown for some proteins, we find that correlations appearing during evolution alone are sufficient to identify key aspects of this design. Finally, we show that the success of this architecture stems from the emergence of soft edge modes recently found to appear near the surface of marginally connected materials. Overall, our in silico evolution experiment offers a window to study the relationship between structure, function, and correlations emerging during evolution. disordered materials | proteins | evolution P roteins are long polymers that can fold in a reproducible way and achieve a specific function. Often, the activity of the main functional site depends on the binding of an effector on a distant site (1, 2). Such an allosteric behavior can occur over large distances, such as 20 residues or more (3), and often involves only a sparse subset of residues in the protein (3, 4). Allosteric regulation offers an appealing target for drug design (5), and there is considerable interest in predicting allosteric pathways (6, 7). One central difficulty is that the physical mechanisms allowing such an "action at a distance" remain elusive. In some cases, allostery can be understood as the modulation of a hinge connecting two extended rigid parts of the protein (8, 9), but, often, the displacement field induced by the binding of the effector cannot be described in these terms (4, 10, 11). Another route, statistical coupling analysis (12), considers correlations within sequences of proteins of the same family to infer allosteric pathways (4, 7). The generality of this elegant approach is, however, debated (13).From a physical viewpoint, specific response at a distance is surprising. The structure of proteins is similar to randomly packed spheres (14). Generically, the response of such systems is nonspecific and decays rapidly in space (in a manner similar to a continuum medium) at distances larger than the particle size; this is true, except close to a critical point where the number of constraints coming from strongly interacting particles is just sufficient to match the number of degrees of freedom of the particles (15). There, the elastic response becomes heterogeneous on all scales (16,17). This point is illustrated in Fig. 1A, showing the rapidly decaying response of a random spring network to a stimulus. However, as shown in Fig. 1B (and independently found in ref. 18 using a different algorithm), springs can be move...

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The unfoldomics decade: an update on intrinsically disordered proteins

Cited by 486 publications

References 165 publications

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

Quantitative mapping of microtubule-associated protein 2c (MAP2c) phosphorylation and regulatory protein 14-3-3ζ-binding sites reveals key differences between MAP2c and its homolog Tau

From protein sequence to dynamics and disorder with DynaMine

Architecture and coevolution of allosteric materials

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