title: Molecular mechanisms of asymmetric RAF dimer activation.
abstract: Protein phosphorylation is one of the most common post-translational modifications in cell regulatory mechanisms. Dimerization plays also a crucial role in the kinase activity of many kinases, including RAF, CDK2 (cyclin-dependent kinase 2) and EGFR (epidermal growth factor receptor), with heterodimers often being the most active forms. However, the structural and mechanistic details of how phosphorylation affects the activity of homo- and hetero-dimers are largely unknown. Experimentally, synthesizing protein samples with fully specified and homogeneous phosphorylation states remains a challenge for structural biology and biochemical studies. Typically, multiple changes in phosphorylation lead to activation of the same protein, which makes structural determination methods particularly difficult. It is also not well understood how the occurrence of phosphorylation and dimerization processes synergize to affect kinase activities. In the present article, we review available structural data and discuss how MD simulations can be used to model conformational transitions of RAF kinase dimers, in both their phosphorylated and unphosphorylated forms.
authors.affiliation: *Department of Chemistry, King's College London, London SE1 1DB, U.K.
authors.forename: Pablo G
authors.initials: PG
authors.lastname: Jambrina
authors.affiliation: *Department of Chemistry, King's College London, London SE1 1DB, U.K.
authors.forename: Olga
authors.initials: O
authors.lastname: Bohuszewicz
authors.affiliation: †School of Physics, University College Dublin, Dublin, Ireland.
authors.forename: Nicolae-Viorel
authors.initials: NV
authors.lastname: Buchete
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: *Department of Chemistry, King's College London, London SE1 1DB, U.K.
authors.forename: Edina
authors.initials: E
authors.lastname: Rosta
mesh_terms: D000818:Animals; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D055503:Protein Multimerization; D048490:raf Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors; D048490:raf Kinases; D051357:Cyclin-Dependent Kinase 2