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

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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.

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Abbreviations

ActRII:

Activin type II receptor

ACVR1:

Activin A type 1 receptor

ALK:

Activin receptor-like kinase

ASA:

Accessible surface area

BMP:

Bone morphogenetic protein

BMPR1A:

Bone morphogenetic protein type 1A receptor or ALK3

BMPRII:

Bone morphogenetic protein type II receptor

BSA:

Buried surface area

ECD:

Extracellular domain

GDF:

Growth/differentiation factor

MISRII:

Mullerian inhibitor substance type II receptor

PP:

Pair potential

TGF-β:

Transforming growth factor-beta

TGFBRI:

Type I TGF-β receptor or ALK5

TGF-βRII:

Type II TGF-β receptor

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Chemical Sciences, Federico II University of Naples, Via Cinthia 45, 80126, Naples, Italy

    Valentina Romano, Luisa Calvanese, Gabriella D’Auria & Lucia Falcigno

  2. Department of Physics, Sapienza University of Rome, P.le A. Moro, 5, 00185, Rome, Italy

    Domenico Raimondo & Anna Tramontano

  3. Institute of Biostructures and Bioimaging—CNR, Via Mezzocannone 16, 80134, Naples, Italy

    Gabriella D’Auria & Lucia Falcigno

Authors
  1. Valentina Romano
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  2. Domenico Raimondo
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  3. Luisa Calvanese
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  4. Gabriella D’Auria
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  5. Anna Tramontano
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  6. Lucia Falcigno
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Corresponding author

Correspondence to Lucia Falcigno.

Additional information

Valentina Romano and Domenico Raimondo contributed equally to this work.

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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)

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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Romano, V., Raimondo, D., Calvanese, L. et al. Toward a better understanding of the interaction between TGF-β family members and their ALK receptors. J Mol Model 18, 3617–3625 (2012). https://doi.org/10.1007/s00894-012-1370-y

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