Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity

Ariane Allain (1) , Isaure Chauvot de Beauchêne (1) , Nicolas Panel (1) , Elodie Laine (2, 1) , Alain Trouvé (3) , Patrice Dubreuil (4) , Luba Tchertanov (1, 3)

1 LBPA - Laboratoire de Biologie et de Pharmacologie Appliquée
2 LCQB-AG - Analytical Genomics [LCQB]
3 CMLA - Centre de Mathématiques et de Leurs Applications
4 CRCM - Centre de Recherche en Cancérologie de Marseille

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.

Mots clés: tyrosine-kinase; allostery; KIT; Point mutation; Cell communication; Biochemical simulations; Substitution mutation; Allosteric regulation; Principal component analysis; Tyrosine kinases; Simulation and modeling

Domaines: Bio-informatique [q-bio.QM]; Biologie moléculaire

Ariane Allain, Isaure Chauvot de Beauchêne, Nicolas Panel, Elodie Laine, Alain Trouvé, et al.. Hotspot mutations in KIT receptor differentially modulate its allosterically coupled conformational dynamics: impact on activation and drug sensitivity. PLoS Computational Biology, 2014, 10 (7), pp.e1003749. ⟨10.1371/journal.pcbi.1003749⟩. ⟨hal-01505833⟩