Differential effects of CSF-1R D802V and KIT D816V homologous mutations on receptor tertiary structure and allosteric communication.
The colony stimulating factor-1 receptor (CSF-1R) and the stem cell factor receptor KIT, type III receptor tyrosine kinases (RTKs), are important mediators of signal transduction. The normal functions of these receptors can be compromised by gain-of-function mutations associated with different physiopatological impacts. Whereas KIT D816V/H mutation is a well-characterized oncogenic event and principal cause of systemic mastocytosis, the homologous CSF-1R D802V has not been identified in human cancers. The KIT D816V oncogenic mutation triggers resistance to the RTK inhibitor Imatinib used as first line treatment against chronic myeloid leukemia and gastrointestinal tumors. CSF-1R is also sensitive to Imatinib and this sensitivity is altered by mutation D802V. Previous in silico characterization of the D816V mutation in KIT evidenced that the mutation caused a structure reorganization of the juxtamembrane region (JMR) and facilitated its departure from the kinase domain (KD). In this study, we showed that the equivalent CSF-1R D802V mutation does not promote such structural effects on the JMR despite of a reduction on some key H-bonds interactions controlling the JMR binding to the KD. In addition, this mutation disrupts the allosteric communication between two essential regulatory fragments of the receptors, the JMR and the A-loop. Nevertheless, the mutation-induced shift towards an active conformation observed in KIT D816V is not observed in CSF-1R D802V. The distinct impact of equivalent mutation in two homologous RTKs could be associated with the sequence difference between both receptors in the native form, particularly in the JMR region. A local mutation-induced perturbation on the A-loop structure observed in both receptors indicates the stabilization of an inactive non-inhibited form, which Imatinib cannot bind.
Laboratoire de Biologie et de Pharmacologie Appliquée, École Normale Supérieure de Cachan, Cachan, France; Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Priscila
P
Da Silva Figueiredo Celestino Gomes
Laboratoire de Biologie et de Pharmacologie Appliquée, École Normale Supérieure de Cachan, Cachan, France.
Nicolas
N
Panel
Laboratoire de Biologie et de Pharmacologie Appliquée, École Normale Supérieure de Cachan, Cachan, France.
Elodie
E
Laine
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Pedro Geraldo
PG
Pascutti
Institut Gustave Roussy, Villejuif, France; Faculty of Medicine, Paris- Sud University, Le Kremlin-Bicêtre, France.
Eric
E
Solary
Laboratoire de Biologie et de Pharmacologie Appliquée, École Normale Supérieure de Cachan, Cachan, France; Centre de Mathématiques et de Leurs Applications, École Normale Supérieure de Cachan, Cachan, France.
Luba
L
Tchertanov
D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry; D005057:Eukaryotic Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D010879:Piperazines / Q000737:chemistry; D025341:Principal Component Analysis; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D016186:Receptor, Macrophage Colony-Stimulating Factor