Influence of phenological barriers and habitat differentiation on the population genetic structure of the balearic endemic Rhamnus ludovici-salvatoris Chodat and R. alaternus L

[EN] Rhamnus ludovici-salvatoris, endemic to the Gymnesian Islands, coexists with the related and widespread R. alaternus in Mallorca and Menorca. In both species, the population genetic structure using RAPD, and flowering during a 3-year period to check for possible phenological barriers, were analyzed. Rhamnus ludovici-salvatoris showed lower genetic diversity and stronger population structure than R. alaternus, the Cabrera population being less diverse and the most differentiated. Rhamnus ludovici-salvatoris flowered one month later, although flowering of both species coincided sporadically. These congeners seem to have diverged through isolation by time and differentiation in habitat. The population genetic structure of R. ludovici-salvatoris could mainly be due to the existence of small populations on the one hand, and a gene flow caused by rare hybridization events on the other, which may also explain the presence of morphologically intermediate individuals in Menorca. 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Mutation D816V Alters the Internal Structure and Dynamics of c-KIT Receptor Cytoplasmic Region: Implications for Dimerization and Activation Mechanisms

The type III receptor tyrosine kinase (RTK) KIT plays a crucial role in the transmission of cellular signals through phosphorylation events that are associated with a switching of the protein conformation between inactive and active states. D816V KIT mutation is associated with various pathologies including mastocytosis and cancers. D816V-mutated KIT is constitutively active, and resistant to treatment with the anti-cancer drug Imatinib. To elucidate the activating molecular mechanism of this mutation, we applied a multi-approach procedure combining molecular dynamics (MD) simulations, normal modes analysis (NMA) and binding site prediction. Multiple 50-ns MD simulations of wild-type KIT and its mutant D816V were recorded using the inactive auto-inhibited structure of the protein, characteristic of type III RTKs. Computed free energy differences enabled us to quantify the impact of D816V on protein stability in the inactive state. We evidenced a local structural alteration of the activation loop (A-loop) upon mutation, and a long-range structural re-organization of the juxta-membrane region (JMR) followed by a weakening of the interaction network with the kinase domain. A thorough normal mode analysis of several MD conformations led to a plausible molecular rationale to propose that JMR is able to depart its auto-inhibitory position more easily in the mutant than in wild-type KIT and is thus able to promote kinase mutant dimerization without the need for extra-cellular ligand binding. Pocket detection at the surface of NMA-displaced conformations finally revealed that detachment of JMR from the kinase domain in the mutant was sufficient to open an access to the catalytic and substrate binding sites