Now showing 1 - 2 of 2
  • Publication
    SARAH Domain-mediated MST2-RASSF Dimeric Interactions
    We model the conformational changes and protein-protein interactions of enzymes involved in signaling along the Hippo pathwaya key molecular mechanism that controls the process of programmed cell death in eukaryotic cells, including cells affected by cancer. Combining modern computational modeling techniques with experimental information from X-ray crystallography and systems biology studies, can unveil detailed molecular interactions and lead to novel drugs. Here, we study the atomistic mechanisms and interactions between MST2 and RASSF-type kinases, through their respective SARAH domains highly conserved, long, terminal α-helices, which play essential roles in the activation of MST kinases and, therefore, in modulating apoptosis. In spite of their key roles in mediating cell signaling pathways, there is little structural information available for the RASSF SARAH domains and their dimerization with the MST2 SARAH domains. In particular, the RASSF1A crystal structure is not available yet. Here, we model, refine and validate atomistic structural models of dimers of the RASSF1A and MST2 SARAH domains, studying the interaction and the dynamic behavior of these molecular complexes using homology modeling, docking and full atomistic molecular dynamics simulations. Experimentally, we validate our approach by designing a novel peptide that can disrupt effectively MST2 homo and hetero SARAH dimers.
      359Scopus© Citations 14
  • Publication
    Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
    RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N-terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC-helix and charged residues upstream of the NtA motif. Additionally, we show that the R-spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure-based mechanism for the auto-transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization-related drug resistance.
      296Scopus© Citations 39