title: SARAH Domain-Mediated MST2-RASSF Dimeric Interactions.
abstract: RASSF enzymes act as key apoptosis activators and tumor suppressors, being downregulated in many human cancers, although their exact regulatory roles remain unknown. A key downstream event in the RASSF pathway is the regulation of MST kinases, which are main effectors of RASSF-induced apoptosis. The regulation of MST1/2 includes both homo- and heterodimerization, mediated by helical SARAH domains, though the underlying molecular interaction mechanism is unclear. Here, we study the interactions between RASSF1A, RASSF5, and MST2 SARAH domains by using both atomistic molecular simulation techniques and experiments. We construct and study models of MST2 homodimers and MST2-RASSF SARAH heterodimers, and we identify the factors that control their high molecular stability. In addition, we also analyze both computationally and experimentally the interactions of MST2 SARAH domains with a series of synthetic peptides particularly designed to bind to it, and hope that our approach can be used to address some of the challenging problems in designing new anti-cancer drugs.
authors.affiliation: School of Physics & Institute for Discovery, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Goar
authors.identifier: http://orcid.org/0000-0002-1390-4004
authors.initials: G
authors.lastname: Sánchez-Sanz
authors.affiliation: School of Physics & Institute for Discovery, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Bartłomiej
authors.identifier: http://orcid.org/0000-0001-5375-1594
authors.initials: B
authors.lastname: Tywoniuk
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|School of Medicine, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Matallanas
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Romano
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Lan K
authors.initials: LK
authors.lastname: Nguyen
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|School of Medicine, University College Dublin, Belfield, Dublin, Ireland.|Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Boris N
authors.initials: BN
authors.lastname: Kholodenko
authors.affiliation: Department of Chemistry, King's College London, London, United Kingdom.
authors.forename: Edina
authors.initials: E
authors.lastname: Rosta
authors.affiliation: Systems Biology Ireland, University College Dublin, Belfield, Dublin, Ireland.|School of Medicine, University College Dublin, Belfield, Dublin, Ireland.|Conway Institute, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Walter
authors.initials: W
authors.lastname: Kolch
authors.affiliation: School of Physics & Institute for Discovery, University College Dublin, Belfield, Dublin, Ireland.
authors.forename: Nicolae-Viorel
authors.identifier: http://orcid.org/0000-0001-9861-1157
authors.initials: NV
authors.lastname: Buchete
mesh_terms: D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000737:chemistry* / Q000648:ultrastructure*; D019281:Dimerization; D029721:Drosophila Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D004789:Enzyme Activation; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D000072417:Protein Domains
chemical_list: C493966:CDKN2B protein, human; D002352:Carrier Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D029721:Drosophila Proteins; C517506:RASSF protein, Drosophila