Dynamic protein–DNA recognition: beyond what can be seen

Fuxreiter, Mónika; Simon, István; Bondos, Sarah E.

doi:10.1016/j.tibs.2011.04.006

Cited by 140 publications

(126 citation statements)

References 98 publications

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“…ID proteins often adopt different conformations, which cannot be determined by conventional methods such as X-ray crystallography (3)(4)(5). Our results provide a rare example showing that the presence of NS309, the most potent channel modulator (38,39), can constrain the freedom of the IDF and turn the unstructured IDF into a well-defined conformation (Fig.…”

Section: Discussionmentioning

confidence: 81%

“…Conformational changes of these domains result in opening of the channel pore. Unlike the well-structured proteins, there are proteins or fragments of proteins that lack well-defined 3D conformations (3)(4)(5)(6)(7)(8). These proteins, termed "intrinsically disordered" (ID) proteins/peptides, typically are flexible in their secondary structures and often can adopt multiple conformations.…”

mentioning

confidence: 99%

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Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Zhang¹,

Pascal²,

Zhang

2013

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

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Most proteins, such as ion channels, form well-organized 3D structures to carry out their specific functions. A typical voltagegated potassium channel subunit has six transmembrane segments (S1-S6) to form the voltage-sensing domain and the pore domain. Conformational changes of these domains result in opening of the channel pore. Intrinsically disordered (ID) proteins/peptides are considered equally important for the protein functions. However, it is difficult to explore the structural features underlying the functions of ID proteins/peptides by conventional methods, such as X-ray crystallography, because of the flexibility of their secondary structures. Unlike voltage-gated potassium channels, families of small-and intermediate-conductance Ca 2+ -activated potassium (SK/IK) channels with important roles in regulating membrane excitability are activated exclusively by Ca 2+ -bound calmodulin (CaM). Upon binding of Ca 2+ to CaM, a 2 × 2 structure forms between CaM and the CaMbinding domain. A channel fragment that connects S6 and the CaMbinding domain is not visible in the protein crystal structure, suggesting that this fragment is an ID fragment. Here we show that the conformation of the ID fragment in SK channels becomes readily identifiable in the presence of NS309, the most potent compound that potentiates the channel activities. This well-defined conformation of the ID fragment, stabilized by NS309, increases the channel open probability at a given Ca 2+ concentration. Our results demonstrate that the ID fragment, itself a target for drugs modulating SK channel activities, plays a unique role in coupling Ca 2+ sensing by CaM and mechanical opening of SK channels.calcium | signaling | gating M ost proteins typically adopt one or more well-defined 3D structures, or domains, to carry out their specific functions. Voltage-gated potassium channels are such an example, with six transmembrane segments (S1-S6) forming the voltage-sensing domain and the pore domain (1, 2). Conformational changes of these domains result in opening of the channel pore. Unlike the well-structured proteins, there are proteins or fragments of proteins that lack well-defined 3D conformations (3-8). These proteins, termed "intrinsically disordered" (ID) proteins/peptides, typically are flexible in their secondary structures and often can adopt multiple conformations. Consequently, the structures of ID proteins are difficult to determine by conventional methods, such as X-ray crystallography, and it is difficult to explore the structural features responsible for functions by ID proteins. Nevertheless, emerging evidence shows that ID proteins/peptides are equally important for the protein functions.Small-and intermediate-conductance Ca 2+

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Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 99%

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Zhang¹,

Pascal²,

Zhang

2013

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

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“…Some PTMs are more frequently found at disordered sites than others 36 (e.g., acetylation and phosphorylation are abundant in the disordered regions of DBPs 37,38 ). In this study, we focus on quantifying the existence of acetylation and phosphorylation modifications in DBPs as these PTMs involve changes to the electrostatic charges of the modified sites in a way that may affect interactions with the negatively charged DNA molecules.…”

Section: The Occurrence Of Acetylation and Phosphorylation At Disordementioning

confidence: 99%

“…This ability to gradually tune the binding affinity was viewed as an "incremental rheostat" rather than as a switch on/off by the modifications 45 . It was shown for Ets-1 that phosphorylation of its disorder tail interferes with formation of intramolecular interactions, which results in a lower binding affinity to DNA 38,45 . The five phosphorylation events on the disordered tail of Ets-1 were reported to attenuate affinity to DNA not by directly affecting its interactions with DNA but by modulating its internal flexibility.…”

Section: The Interplay Between Post-translational Modifications Of DImentioning

confidence: 99%

Modulating Protein–dna Interactions by Post-Translational Modifications at Disordered Regions

Vuzman

Hoffman²,

Levy

2011

Biocomputing 2012

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Intrinsically disordered regions, particularly disordered tails, are very common in DNA-binding proteins (DBPs). The ability of disordered tails to modulate specific and nonspecific interactions with DNA is tightly linked to their being rich in positively charged residues that are often non-randomly distributed along the tail. Perturbing the composition and distribution of charged residues in the disordered regions by post-translational modifications, such as phosphorylation and acetylation, may impair the ability of the tail to interact nonspecifically with DNA by reducing its DNA affinity. In this study, we analyzed datasets of 3398 and 8943 human proteins that undergo acetylation or phosphorylation, respectively. Both modifications are common on the disordered tails of DBPs (3.1 ± 0.2 (0.07 ± 0.007) and 2.0 ± 0.2 (0.02 ± 0.003) acetylation and phosphorylation sites per tail (per tail residue), respectively). Phosphorylation sites are abundant in disordered regions and particularly in flexible tails for both DBPs and non-DBPs. While acetylation sites are also frequently occurred in the disordered tails of DBPs, in non-DBPs they are often found in ordered regions. This difference may indicate that acetylation has different function in DBPs and non-DBPs. Post-translational modifications, which often take place at disordered sites of DBPs, can modulate the interactions of proteins with DNA by changing the local and global properties of the tails. The effect of the modulation can be tuned by adjusting the number of modifications and the cross-talks between them.

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“…IDPs and IDRs are nevertheless frequently involved in essential biological activities, such as cell cycle control and cellular signal transduction, transcriptional and translational regulation, membrane fusion and control pathways [4]. Intrinsic disorder enables a number of capabilities of a protein and therefore participates in molecular recognition, molecular assembly and protein modification [5], [6] via protein-protein, protein-nucleic acid and protein-ligand interactions [7], [8]. Disorder proteins are also found to play key role in critical human diseases [9], [10], such as cancer, AIDS, amyloidoses, cardiovascular and neurodegenerative diseases, genetic diseases, as well as in drug development [11].…”

Section: Introductionmentioning

confidence: 99%

Improved protein disorder predictor by smoothing output

Iqbal¹,

Islam²,

Hoque³

2014

2014 17th International Conference on Computer and Information Technology (ICCIT)

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Abstract-Intrinsically disorder regions (IDRs) or, proteins (IDPs) are associated with important biological functions, while lacking stable structure in their native state. The phenomena of disordered proteins or residues are abundant in nature and are extensively involved in critical human diseases and hence impacting drug discovery. Thus, the study using disorder prediction is becoming crucial in the proteomic research. The large scale growth of genome database demands high performance computational methods for identification of protein disorder. We developed a canonical support vector machine based disorder predictor, DisPredict by integrating RBF kernel. It employs novel feature set for accurate characterization of disorder which outperformed two leading predictors: the neural network based SPINE-D and Meta predictor MFDp based on ten-fold cross validation. We propose a post processing of probabilities to further improve the accuracy, named DisPredict1.1 which yields outstanding performance further both in binary annotation and real valued probability prediction per residue in both short and long disordered regions. It provides highest Mathews Correlation Coefficient (MCC), competitive Area Under receiver operating characteristic Curve (AUC) and lowest Mean Absolute Error (MAE) when compared with twenty existing predictors of several kinds on independent benchmark dataset. DisPredict is available online.

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Dynamic protein–DNA recognition: beyond what can be seen

Cited by 140 publications

References 98 publications

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Modulating Protein–dna Interactions by Post-Translational Modifications at Disordered Regions

Improved protein disorder predictor by smoothing output

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Dynamic protein–DNA recognition: beyond what can be seen

Cited by 140 publications

References 98 publications

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca 2+ -sensing and SK channel activation

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca 2+ -sensing and SK channel activation

Modulating Protein–dna Interactions by Post-Translational Modifications at Disordered Regions

Improved protein disorder predictor by smoothing output

Contact Info

Product

Resources

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Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation

Unstructured to structured transition of an intrinsically disordered protein peptide in coupling Ca ²⁺ -sensing and SK channel activation