title: Toward a better understanding of the interaction between TGF-β family members and their ALK receptors.
abstract: Transforming growth factor-beta (TGF-β) proteins are a family of structurally related extracellular proteins that trigger their signaling functions through interaction with the extracellular domains of their cognate serine/threonine kinase receptors. The specificity of TGF-β/receptor binding is complex and gives rise to multiple functional roles. Additionally, it is not completely understood at the atomic level. Here, we use the most reliable computational methods currently available to study systems involving activin-like kinase (ALK) receptors ALK4 and ALK7 and their multiple TGF-β ligands. We built models for all these proteins and their complexes for which experimental structures are not available. By analyzing the surfaces of interaction in six different TGF-β/ALK complexes we could infer which are the structural distinctive features of the ligand-receptor binding mode. Furthermore, this study allowed us to rationalize why binding of the growth factors GDF3 and Nodal to the ALK4 receptor requires the Cripto co-factor, whilst binding to the ALK7 receptor does not.
authors.affiliation: Department of Chemical Sciences, Federico II University of Naples, Via Cinthia 45, 80126, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Romano
authors.forename: Domenico
authors.initials: D
authors.lastname: Raimondo
authors.forename: Luisa
authors.initials: L
authors.lastname: Calvanese
authors.forename: Gabriella
authors.initials: G
authors.lastname: D'Auria
authors.forename: Anna
authors.initials: A
authors.lastname: Tramontano
authors.forename: Lucia
authors.initials: L
authors.lastname: Falcigno
mesh_terms: D030201:Activin Receptors, Type I / Q000737:chemistry*; D001665:Binding Sites; D003198:Computer Simulation; D055412:Growth Differentiation Factors / Q000737:chemistry*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D055457:Nodal Protein / Q000737:chemistry*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D055411:TGF-beta Superfamily Proteins / Q000737:chemistry
chemical_list: D055412:Growth Differentiation Factors; C526007:NODAL protein, human; D055457:Nodal Protein; D055411:TGF-beta Superfamily Proteins; C498932:ACVR1B protein, human; C424205:ACVR1C protein, human; D030201:Activin Receptors, Type I