The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT

Julie Ledoux
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  • PersonId : 1118293
Alain Trouvé
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  • PersonId : 1118294
Luba Tchertanov

Résumé

RTK KIT regulates a variety of crucial cellular processes via its cytoplasmic domain (CD), which is composed of the tyrosine kinase domain, crowned by the highly flexible domains-the juxtamembrane region, kinase insertion domain, and C-tail, which are key recruitment regions for downstream signalling proteins. To prepare a structural basis for the characterization of the interactions of KIT with its signalling proteins (KIT INTERACTOME), we generated the 3D model of the full-length CD attached to the transmembrane helix. This generic model of KIT in inactive state was studied by molecular dynamics simulation under conditions mimicking the natural environment of KIT. With the accurate atomistic description of the multidomain KIT dynamics, we explained its intrinsic (intra-domain) and extrinsic (inter-domain) disorder and represented the conformational assemble of KIT through free energy landscapes. Strongly coupled movements within each domain and between distant domains of KIT prove the functional interdependence of these regions, described as allosteric regulation, a phenomenon widely observed in many proteins. We suggested that KIT, in its inactive state, encodes all properties of the active protein and its post-transduction events.
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Dates et versions

hal-03605085 , version 1 (10-03-2022)

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Julie Ledoux, Alain Trouvé, Luba Tchertanov. The Inherent Coupling of Intrinsically Disordered Regions in the Multidomain Receptor Tyrosine Kinase KIT. International Journal of Molecular Sciences, 2022, 23 (3), pp.1589. ⟨10.3390/ijms23031589⟩. ⟨hal-03605085⟩
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