Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations
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...
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MDPI AG
2021-07-01
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| author | Julie Ledoux Alain Trouvé Luba Tchertanov |
| author_facet | Julie Ledoux Alain Trouvé Luba Tchertanov |
| author_sort | Julie Ledoux |
| collection | DOAJ |
| description | 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 3<sub>10</sub>-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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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T09:37:33Z |
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| spelling | doaj.art-b48461644fd843b4ac9b5cc6774a219a2023-11-22T03:57:32ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-07-012214737510.3390/ijms22147375Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics SimulationsJulie Ledoux0Alain Trouvé1Luba Tchertanov2Centre Borelli, CNRS, ENS Paris-Saclay, Université Paris-Saclay, 4 Avenue des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, CNRS, ENS Paris-Saclay, Université Paris-Saclay, 4 Avenue des Sciences, F-91190 Gif-sur-Yvette, FranceCentre Borelli, CNRS, ENS Paris-Saclay, Université Paris-Saclay, 4 Avenue des Sciences, F-91190 Gif-sur-Yvette, FranceThe 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 3<sub>10</sub>-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.https://www.mdpi.com/1422-0067/22/14/7375receptor tyrosine kinaseRTKKIT cytoplasmic regionkinase insert domainKIDmolecular dynamics and folding |
| spellingShingle | Julie Ledoux Alain Trouvé Luba Tchertanov Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations International Journal of Molecular Sciences receptor tyrosine kinase RTK KIT cytoplasmic region kinase insert domain KID molecular dynamics and folding |
| title | Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations |
| title_full | Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations |
| title_fullStr | Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations |
| title_full_unstemmed | Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations |
| title_short | Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations |
| title_sort | folding and intrinsic disorder of the receptor tyrosine kinase kit insert domain seen by conventional molecular dynamics simulations |
| topic | receptor tyrosine kinase RTK KIT cytoplasmic region kinase insert domain KID molecular dynamics and folding |
| url | https://www.mdpi.com/1422-0067/22/14/7375 |
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