title: Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity.
abstract: Receptor tyrosine kinase KIT controls many signal transduction pathways and represents a typical allosterically regulated protein. The mutation-induced deregulation of KIT activity impairs cellular physiological functions and causes serious human diseases. The impact of hotspots mutations (D816H/Y/N/V and V560G/D) localized in crucial regulatory segments, the juxtamembrane region (JMR) and the activation (A-) loop, on KIT internal dynamics was systematically studied by molecular dynamics simulations. The mutational outcomes predicted in silico were correlated with in vitro and in vivo activation rates and drug sensitivities of KIT mutants. The allosteric regulation of KIT in the native and mutated forms is described in terms of communication between the two remote segments, JMR and A-loop. A strong correlation between the communication profile and the structural and dynamical features of KIT in the native and mutated forms was established. Our results provide new insight on the determinants of receptor KIT constitutive activation by mutations and resistance of KIT mutants to inhibitors. Depiction of an intra-molecular component of the communication network constitutes a first step towards an integrated description of vast communication pathways established by KIT in physiopathological contexts.
authors: Bioinformatics, Molecular Dynamics & Modeling (BiMoDyM), Laboratoire de Biologie et Pharmacologie Appliqués (LBPA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Isaure
authors: I
authors: Chauvot de Beauchêne
authors: Bioinformatics, Molecular Dynamics & Modeling (BiMoDyM), Laboratoire de Biologie et Pharmacologie Appliqués (LBPA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Ariane
authors: A
authors: Allain
authors: Bioinformatics, Molecular Dynamics & Modeling (BiMoDyM), Laboratoire de Biologie et Pharmacologie Appliqués (LBPA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Nicolas
authors: N
authors: Panel
authors: Bioinformatics, Molecular Dynamics & Modeling (BiMoDyM), Laboratoire de Biologie et Pharmacologie Appliqués (LBPA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Elodie
authors: E
authors: Laine
authors: Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Alain
authors: A
authors: Trouvé
authors: Inserm, U1068, Signaling, Hematopoiesis and Mechanism of Oncogenesis (CRCM); Institut Paoli-Calmettes; Aix-Marseille University; CNRS, UMR7258, Marseille, France.
authors: Patrice
authors: P
authors: Dubreuil
authors: Bioinformatics, Molecular Dynamics & Modeling (BiMoDyM), Laboratoire de Biologie et Pharmacologie Appliqués (LBPA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France; Centre de Mathématiques et de Leurs Applications (CMLA-CNRS), Ecole Normale Supérieure de Cachan, Cachan, France.
authors: Luba
authors: L
authors: Tchertanov
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation / Q000235:genetics*; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D019009:Proto-Oncogene Proteins c-kit