MobiDB-lite: Fast and highly specific consensus prediction of intrinsic disorder in proteins

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.

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Is the intrinsic disorder of proteins the cause of the scale-free architecture of protein–protein interaction networks?

PROTEOMICS ◽

10.1002/pmic.200600455 ◽

2007 ◽

Vol 7 (6) ◽

pp. 961-964 ◽

Cited By ~ 15

Author(s):

Santiago Schnell ◽

Santo Fortunato ◽

Sourav Roy

Keyword(s):

Protein Interaction ◽

Intrinsic Disorder ◽

Protein Interaction Networks ◽

Interaction Networks ◽

Scale Free ◽

Protein Protein Interaction ◽

Protein Protein Interaction Networks

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Intrinsic disorder in the androgen receptor: identification, characterisation and drugability

Molecular BioSystems ◽

10.1039/c1mb05249g ◽

2012 ◽

Vol 8 (1) ◽

pp. 82-90 ◽

Cited By ~ 41

Author(s):

Iain J. McEwan

Keyword(s):

Androgen Receptor ◽

Intrinsic Disorder

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Visualising intrinsic disorder and conformational variation in protein ensembles

Faraday Discussions ◽

10.1039/c3fd00138e ◽

2014 ◽

Vol 169 ◽

pp. 179-193 ◽

Cited By ~ 6

Author(s):

Julian Heinrich ◽

Michael Krone ◽

Seán I. O'Donoghue ◽

Daniel Weiskopf

Keyword(s):

Intrinsic Disorder ◽

Molecular Graphics ◽

Post Translational Modifications ◽

3D Structures ◽

Intrinsically Disordered ◽

Intrinsically Disordered Regions ◽

Wide Range ◽

Conformational Variations ◽

Protein Ensembles ◽

Traditional Approaches

Intrinsically disordered regions (IDRs) in proteins are still not well understood, but are increasingly recognised as important in key biological functions, as well as in diseases. IDRs often confound experimental structure determination—however, they are present in many of the available 3D structures, where they exhibit a wide range of conformations, from ill-defined and highly flexible to well-defined upon binding to partner molecules, or upon post-translational modifications. Analysing such large conformational variations across ensembles of 3D structures can be complex and difficult; our goal in this paper is to improve this situation by augmenting traditional approaches (molecular graphics and principal components) with methods from human–computer interaction and information visualisation, especially parallel coordinates. We present a new tool integrating these approaches, and demonstrate how it can dissect ensembles to reveal functional insights into conformational variation and intrinsic disorder.

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