Journal of Molecular Modeling

, Volume 18, Issue 8, pp 3617–3625 | Cite as

Toward a better understanding of the interaction between TGF-β family members and their ALK receptors

  • Valentina Romano
  • Domenico Raimondo
  • Luisa Calvanese
  • Gabriella D’Auria
  • Anna Tramontano
  • Lucia FalcignoEmail author
Original Paper


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.


Comparative modeling TGF-β protein ALK receptor Protein–protein docking 



Activin type II receptor


Activin A type 1 receptor


Activin receptor-like kinase


Accessible surface area


Bone morphogenetic protein


Bone morphogenetic protein type 1A receptor or ALK3


Bone morphogenetic protein type II receptor


Buried surface area


Extracellular domain


Growth/differentiation factor


Mullerian inhibitor substance type II receptor


Pair potential


Transforming growth factor-beta


Type I TGF-β receptor or ALK5


Type II TGF-β receptor



King Abdullah University of Science and Technology (KAUST; Award No. KUK-I1-012-43); Fondazione Roma and the Italian Ministry of Health (contract no.onc_ord 25/07, FIRB ITALBIONET and PROTEOMICA).

Ministero dell’Università e della Ricerca Scientifica (MIUR), project PRIN n° prot. 2008F5A3AF_001.

Supplementary material

894_2012_1370_MOESM1_ESM.pdf (33 kb)
Fig. S1 Topology diagrams of a TGF-β protein (a) and of the extracellular domain of an ALK receptor (b). In both schemes, the β-strands are represented by large arrows in pink and the α-helices are shown as red cylinders. The small blue arrows indicate the directionality of the protein chain, from the N-terminus to the C-terminus. (PDF 33 kb)
894_2012_1370_MOESM2_ESM.pdf (39 kb)
Fig. S2 The target–template sequence alignments obtained by HHpred of (a) GDF3 (UniProt ID: Q9NR23) and BMP2, (b) GDF11 (UniProt ID: O95390) and GDF8, (c), ALK4-ECD (UniProt ID: P36896) and ALK5-ECD , (d) ALK7-ECD (UniProt ID: Q8NER5) with ALK5-ECD and ALK3-loop 23. Shaded columns Conserved residues. (PDF 38 kb)


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Valentina Romano
    • 1
  • Domenico Raimondo
    • 2
  • Luisa Calvanese
    • 1
  • Gabriella D’Auria
    • 1
    • 3
  • Anna Tramontano
    • 2
  • Lucia Falcigno
    • 1
    • 3
    Email author
  1. 1.Department of Chemical SciencesFederico II University of NaplesNaplesItaly
  2. 2.Department of PhysicsSapienza University of RomeRomeItaly
  3. 3.Institute of Biostructures and Bioimaging—CNRNaplesItaly

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