Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor(456 views) Calvanese L, Saporito A, Oliva R, D'Auria G, Pedone C, Paolillo L, Ruvo M, Marasco D, Falcigno L
Keywords: Conformational Analysis, Docking, Egf-Cfc Family, Homology Modelling, Activin, Activin Receptor, Cysteine, Disulfide, Epidermal Growth Factor, Protein, Protein Cripto, Transforming Growth Factor Beta, Unclassified Drug, Acvr1b Protein, Human, Membrane Protein, Tdgf1 Protein, Tumor Protein, Binding Affinity, Carcinogenesis, Conference Paper, Controlled Study, Embryo Development, Molecular Docking, Molecular Interaction, Mutagenesis, Nuclear Magnetic Resonance, Priority Journal, Protein Domain, Protein Expression, Protein Protein Interaction, Structure Analysis, Synthesis, Amino Acid Sequence, Article, Chemistry, High Performance Liquid Chromatography, Mass Spectrometry, Metabolism, Molecular Genetics, Nuclear Magnetic Resonance Spectroscopy, Protein Binding, Protein Secondary Structure, Protein Tertiary Structure, Type I, High Pressure Liquid, Membrane Glycoproteins, Molecular Sequence Data, Neoplasm Proteins, Protein Structure, Type I Chemistry Metabolism, Epidermal Growth Factor Chemistry Metabolism, Gpi-Linked Proteins, Intercellular Signaling Peptides And Proteins, Membrane Glycoproteins Chemistry Metabolism, Neoplasm Proteins Chemistry Metabolism,
Affiliations: *** IBB - CNR ***
Dipartimento di Chimica, Universita Federico II, Complesso Universitario MSA, via Cintia 45, 80126, Napoli, Italy.
Istituto di Biostrutture e Bioimmagini, CNR, via Mezzocannone 16, 80134 Napoli, Italy
Dipartimento di Scienze Applicate, Università degli Studi di Napoli Parthenope, Centro Direzionale Isola C4, 80143 Napoli, Italy
References: Schiffer, S.G., Foley, S., Kaffashan, A., Hronowski, X., Zichittella, A.E., Yeo, C.Y., Miatkowski, K., Williams, K.P., Fucosylation of Cripto is required for its ability to facilitate nodal signaling (2001) J. Biol. Chem, 276 (41), pp. 37769-3777
Yan, Y.T., Liu, J.J., Luo, Y.E.C., Haltiwanger, R.S., Abate-Shen, C., Shen, M.M., Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway (2002) Mol. Cell Biol, 22 (13), pp. 4439-4449
Adkins, H.B., Bianco, C., Schiffer, S.G., Rayhorn, P., Zafari, M., Cheung, A.E., Orozco, O., Sanicola, M., Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo (2003) J. Clin. Invest, 112 (4), pp. 575-587
Saloman, D.S., Bianco, C., Ebert, A.D., Khan, N.I., De Santis, M., Normanno, N., Wechselberger, C., Persico, G., The EGF-CFC family: Novel epidermal growth factor-related proteins in development and cancer (2000) Endocr. Relat. Cancer, 7 (4), pp. 199-226
Shen, M.M., Decrypting the role of Cripto in tumorigenesis (2003) J. Clin. Invest, 112 (4), pp. 500-502
Parisi, S., D'Andrea, D., Lago, C.T., Adamson, E.D., Persico, M.G., Minchiotti, G., Nodal-dependent Cripto signaling promotes cardiomyogenesis and redirects the neural fate of embryonic stem cells (2003) J. Cell Biol, 163 (2), pp. 303-314
Sakuma, R., Ohnishi Yi, Y., Meno, C., Fujii, H., Juan, H., Takeuchi, J., Ogura, T., Hamada, H., Inhibition of Nodal signalling by Lefty mediated through interaction with common receptors and efficient diffusion (2002) Genes Cells, 7 (4), pp. 401-412
Schier, A.F., Nodal signaling in vertebrate development (2003) Annu. Rev. Cell Dev. Biol, 19, pp. 589-621
Yeo, C., Whitman, M., Nodal signals to Smads through Cripto-dependent and Cripto-independent mechanisms (2001) Mol. Cells, 7 (5), pp. 949-957
Chen, C., Ware, S.M., Sato, A., Houston-Hawkins, D.E., Habas, R., Matzuk, M.M., Shen, M.M., Brown, C.W., The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo (2006) Development, 133 (2), pp. 319-329
Cheng, S.K., Olale, F., Bennett, J.T., Brivanlou, A.H., Schier, A.F., EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1 (2003) Genes Dev, 17 (1), pp. 31-36
Gray, P.C., Harrison, C.A., Vale, W., Cripto forms a complex with activin and type II activin receptors and can block activin signaling (2003) Proc. Natl. Acad. Sci. U.S.A, 100 (9), pp. 5193-5198
Marasco, D., Saporito, A., Ponticelli, S., Chambery, A., De Falco, S., Pedone, C., Minchiotti, G., Ruvo, M., Chemical synthesis ofmouse cripto CFC variants (2006) Proteins, 64 (3), pp. 779-788
Risbridger, G.P., Schmitt, J.F., Robertson, D.M., Activins and inhibins in endocrine and other tumors (2001) Endocr. Rev, 22 (6), pp. 836-858
Shani, G., Fischer, W.H., Justice, N.J., Kelber, J.A., Vale, W., Gray, P.C., GRP78 and Cripto form a complex at the cell surface and collaborate to inhibit transforming growth factor beta signalling and enhance cell growth (2008) Mol. Cell Biol, 28 (2), pp. 666-677
Bianco, C., Normanno, N., Salomon, D.S., Ciardiello, F., Role of the cripto (EGF-CFC) family in embryogenesis and cancer (2004) Growth Factors, 22 (3), pp. 133-139
Gray, P.C., Shani, G., Aung, K., Kelber, J., Vale, W., Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signalling (2006) Mol. Cell Biol, 26 (24), pp. 9268-9278
Lin, S.J., Lerch, T.F., Cook, R.W., Jardetzky, T.S., Woodruff, T.K., The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding (2006) Reproduction, 132 (2), pp. 179-190
Calvanese, L., Saporito, A., Marasco, D., D'Auria, G., Minchiotti, G., Pedone, C., Paolillo, L., Ruvo, M., Solution structure of mouse Cripto CFC domain and its inactive variant Trp107Ala (2006) J. Med. Chem, 49 (24), pp. 7054-7062
Kirsch, T., Sebald, W., Dreyer, M.K., Crystal structure of the BMP-2-BRIA ectodomain complex (2000) Nat. Struct. Biol, 7 (6), pp. 492-496
Fields, G.B., Noble, R.L., Solid phase peptide synthesis utilizing 9- fluorenylmethoxycarbonyl amino acids (1990) Int. J. Pept. Protein Res, 35 (3), pp. 161-214
Bax, A., Davis, D.G., MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy (1985) J. Magn. Reson, 65, pp. 355-360
Bax, A., Practical aspects of two-dimensional transverse NOE spectroscopy (1985) J. Magn. Reson, 63, pp. 207-213
States, D.J., Haberhorn, R.A., Ruben, D.J., A two-dimensional nuclear Overhauser experiment with pure absorption phase in four quadrants (1982) J. Magn. Reson, 48, pp. 286-292
Piotto, M., Saudek, V., Sklenar, V., Gradient-tailored excitation for single-quantum NMR spectroscopy of aqueous solutions (1992) J. Biomol. NMR, 2 (6), pp. 661-665
Delaglio, F., Grzesiek, S., Vuister, G.W., Zhu, G., Pfeifer, J., Bax, A., NMRPipe: A multidimensional spectral processing system based on UNIX pipes (1995) J. Biomol. NMR, 6 (3), pp. 277-293
Johnson, B.A., Using NMRView to visualize and analyze the NMR spectra of macromolecules (2004) Methods Mol. Biol, 278, pp. 313-352
Wuthrich, K., (1986) NMR of Proteins and Nucleic Acids, , Wiley: New York
Guntert, P., Braun, W., Wuthrich, K., Efficient computation of three-dimensional protein structures in solution from nuclear magnetic resonance data using the program DIANA and the supporting programs CALIBA, HABAS and GLOMSA (1991) J. Mol. Biol, 217 (3), pp. 517-530
Guntert, P., Mumenthaler, C., Wuthrich, K., Torsion angle dynamics for NMR structure calculation with the new program DYANA (1997) J. Mol. Biol, 273, pp. 283-298
Guntert, P., Automated NMR structure calculation with CYANA (2004) Methods Mol. Biol, 278, pp. 353-378
Pearlman DA, Case DA, Caldwell JW, Ross WS, Cheatham TE, III, DeBolt S, Ferguson D, Seibel G, Kollman P. AMBER, a package of computer program for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules. Comp Phys Commun 1995
91: 1-41Koradi, R., Billeter, M., Wuthrich, K., MOLMOL: A program for display and analysis of macromolecular structures (1996) J. Mol. Graphics, 14 (1), pp. 29-32. , 51-55
Altschul, S.F., Madden, T.L., Schaffer, A.A., Zhang, J., Zhang, Z., Miller, W., Lipman, D.J., Gapped BLAST and PSI-BLAST: A new generation of protein database search programs (1997) Nucleic Acids Res, 25 (17), pp. 3389-3402
Finn RD, Mistry J, Schuster-Bockler B, Griffiths-Jones S, Hollich V, Lassmann T, Moxon S, Marshall M, Khanna A, Durbin R, Eddy SR, Sonnhammer EL, Bateman A. Pfam: clans, web tools and services. Nucleic Acids Res. 2006
34: (Database issue): D247-D251Soding, J., Protein homology detection by HMM-HMM comparison (2005) Bioinformatics, 21 (7), pp. 951-960
Soding, J., Biegert, A., Lupas, A.N., The HHpred interactive server for protein homology detection and structure prediction (2005) Nucleic Acids Res, 33. , Web Server issue, W244-W248
Jones, D.T., GenTHREADER: An efficient and reliable protein fold recognition method for genomic sequences (1999) J. Mol. Biol, 287 (4), pp. 797-815
Thompson, J.D., Higgins, D.G., Gibson, T.J., CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice (1994) Nucleic Acids Res, 22 (22), pp. 4673-4680
Sali, A., Blundell, T.L., Comparative protein modelling by satisfaction of spatial restraints (1993) J. Mol. Biol, 234 (3), pp. 779-815
Hooft, R.W., Vriend, G., Sander, C., Abola, E.E., Errors in protein structures (1996) Nature, 381 (6580), p. 272
Vriend G. WHAT IF: a molecular modelling and drug design program. J. Mol. Graphics 1990
8(1): 52-56, 29Bowie, J.U., Luthy, R., Eisenberg, D., A method to identify protein sequences that fold into a known three-dimensional structure (1991) Science, 253 (5016), pp. 164-170
Luthy, R., Bowie, J.U., Eisenberg, D., Assessment of protein models with three-dimensional profiles (1992) Nature, 356 (6364), pp. 83-85
Wallner, B., Elofsson, A., Can correct protein models be identified? (2003) Protein Sci, 12 (5), pp. 1073-1086
Gabb, H.A., Jackson, R.M., Sternberg, M.J., Modelling protein docking using shape complementarity, electrostatics and biochemical information (1997) J. Mol. Biol, 272 (1), pp. 106-120
Moont, G., Gabb, H.A., Sternberg, M.J., Use of pair potentials across protein interfaces in screening predicted docked complexes (1999) Proteins, 35 (3), pp. 364-373
Jackson, R.M., Gabb, H.A., Sternberg, M.J., Rapid refinement of protein interfaces incorporating solvation: Application to the docking problem (1998) J. Mol. Biol, 276 (1), pp. 265-285
Minchiotti, G., Manco, G., Parisi, S., Lago, C.T., Rosa, F., Persico, M.G., Structure-function analysis of the EGF-CFC family member Cripto identifies residues essential for nodal signalling (2001) Development, 128 (22), pp. 4501-4510
Wishart, D.S., Sykes, B.D., Richards, F.M., Relationship between nuclear magnetic resonance chemical shift and protein secondary structure (1991) J. Mol. Biol, 222 (2), pp. 311-333
Foley, S.F., van Vlijmen, H.W., Boynton, R.E., Adkins, H.B., Cheung, A.E., Singh, J., Sanicola, M., Wen, D., The CRIPTO/FRL-1/CRYPTIC (CFC) domain of human Cripto. Functional and structural insights through disulfide structure analysis (2003) Eur. J. Biochem, 270 (17), pp. 3610-3618
Kingsley, D.M., The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms (1994) Genes Dev, 8 (2), pp. 133-146
Harrison, C.A., Gray, P.C., Koerber, S.C., Fischer, W., Vale, W., Identification of a functional binding site for activin on the type I receptor ALK4 (2003) J. Biol. Chem, 278 (23), pp. 21129-21135
Innis, C.A., Shi, J., Blundell, T.L., Evolutionary trace analysis of TGF-beta and related growth factors: Implications for site-directed mutagenesis (2000) Protein Eng, 13 (12), pp. 839-847
Sternberg, M.J., Gabb, H.A., Jackson, R.M., Moont, G., Protein-protein docking. Generation and filtering of complexes (2000) Methods Mol. Biol, 143, pp. 399-415
Fernandez-Recio, J., Romero, A., Sancho, J., Energetics of a hydrogen bond (charged and neutral) and of a cation-pi interaction in apoflavodoxin (1999) J. Mol. Biol, 290 (1), pp. 319-330
Meurisse, R., Brasseur, R., Thomas, A., Aromatic side-chain interactions in proteins. Near- and far-sequence His-X pairs (2003) Biochim. Biophys. Acta, 1649 (1), pp. 85-96
Schiffer, S. G., Foley, S., Kaffashan, A., Hronowski, X., Zichittella, A. E., Yeo, C. Y., Miatkowski, K., Williams, K. P., Fucosylation of Cripto is required for its ability to facilitate nodal signaling (2001) J. Biol. Chem, 276 (41), pp. 37769-3777
Yan, Y. T., Liu, J. J., Luo, Y. E. C., Haltiwanger, R. S., Abate-Shen, C., Shen, M. M., Dual roles of Cripto as a ligand and coreceptor in the nodal signaling pathway (2002) Mol. Cell Biol, 22 (13), pp. 4439-4449
Adkins, H. B., Bianco, C., Schiffer, S. G., Rayhorn, P., Zafari, M., Cheung, A. E., Orozco, O., Sanicola, M., Antibody blockade of the Cripto CFC domain suppresses tumor cell growth in vivo (2003) J. Clin. Invest, 112 (4), pp. 575-587
Saloman, D. S., Bianco, C., Ebert, A. D., Khan, N. I., De Santis, M., Normanno, N., Wechselberger, C., Persico, G., The EGF-CFC family: Novel epidermal growth factor-related proteins in development and cancer (2000) Endocr. Relat. Cancer, 7 (4), pp. 199-226
Shen, M. M., Decrypting the role of Cripto in tumorigenesis (2003) J. Clin. Invest, 112 (4), pp. 500-502
Schier, A. F., Nodal signaling in vertebrate development (2003) Annu. Rev. Cell Dev. Biol, 19, pp. 589-621
Chen, C., Ware, S. M., Sato, A., Houston-Hawkins, D. E., Habas, R., Matzuk, M. M., Shen, M. M., Brown, C. W., The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo (2006) Development, 133 (2), pp. 319-329
Cheng, S. K., Olale, F., Bennett, J. T., Brivanlou, A. H., Schier, A. F., EGF-CFC proteins are essential coreceptors for the TGF-beta signals Vg1 and GDF1 (2003) Genes Dev, 17 (1), pp. 31-36
Gray, P. C., Harrison, C. A., Vale, W., Cripto forms a complex with activin and type II activin receptors and can block activin signaling (2003) Proc. Natl. Acad. Sci. U. S. A, 100 (9), pp. 5193-5198
Risbridger, G. P., Schmitt, J. F., Robertson, D. M., Activins and inhibins in endocrine and other tumors (2001) Endocr. Rev, 22 (6), pp. 836-858
Gray, P. C., Shani, G., Aung, K., Kelber, J., Vale, W., Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signalling (2006) Mol. Cell Biol, 26 (24), pp. 9268-9278
Lin, S. J., Lerch, T. F., Cook, R. W., Jardetzky, T. S., Woodruff, T. K., The structural basis of TGF-beta, bone morphogenetic protein, and activin ligand binding (2006) Reproduction, 132 (2), pp. 179-190
Fields, G. B., Noble, R. L., Solid phase peptide synthesis utilizing 9- fluorenylmethoxycarbonyl amino acids (1990) Int. J. Pept. Protein Res, 35 (3), pp. 161-214
Bax, A., Davis, D. G., MLEV-17-based two-dimensional homonuclear magnetization transfer spectroscopy (1985) J. Magn. Reson, 65, pp. 355-360
States, D. J., Haberhorn, R. A., Ruben, D. J., A two-dimensional nuclear Overhauser experiment with pure absorption phase in four quadrants (1982) J. Magn. Reson, 48, pp. 286-292
Johnson, B. A., Using NMRView to visualize and analyze the NMR spectra of macromolecules (2004) Methods Mol. Biol, 278, pp. 313-352
Altschul, S. F., Madden, T. L., Schaffer, A. A., Zhang, J., Zhang, Z., Miller, W., Lipman, D. J., Gapped BLAST and PSI-BLAST: A new generation of protein database search programs (1997) Nucleic Acids Res, 25 (17), pp. 3389-3402
Jones, D. T., GenTHREADER: An efficient and reliable protein fold recognition method for genomic sequences (1999) J. Mol. Biol, 287 (4), pp. 797-815
Thompson, J. D., Higgins, D. G., Gibson, T. J., CLUSTAL W: Improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice (1994) Nucleic Acids Res, 22 (22), pp. 4673-4680
Hooft, R. W., Vriend, G., Sander, C., Abola, E. E., Errors in protein structures (1996) Nature, 381 (6580), p. 272
8 (1): 52-56, 29Bowie, J. U., Luthy, R., Eisenberg, D., A method to identify protein sequences that fold into a known three-dimensional structure (1991) Science, 253 (5016), pp. 164-170
Gabb, H. A., Jackson, R. M., Sternberg, M. J., Modelling protein docking using shape complementarity, electrostatics and biochemical information (1997) J. Mol. Biol, 272 (1), pp. 106-120
Jackson, R. M., Gabb, H. A., Sternberg, M. J., Rapid refinement of protein interfaces incorporating solvation: Application to the docking problem (1998) J. Mol. Biol, 276 (1), pp. 265-285
Wishart, D. S., Sykes, B. D., Richards, F. M., Relationship between nuclear magnetic resonance chemical shift and protein secondary structure (1991) J. Mol. Biol, 222 (2), pp. 311-333
Foley, S. F., van Vlijmen, H. W., Boynton, R. E., Adkins, H. B., Cheung, A. E., Singh, J., Sanicola, M., Wen, D., The CRIPTO/FRL-1/CRYPTIC (CFC) domain of human Cripto. Functional and structural insights through disulfide structure analysis (2003) Eur. J. Biochem, 270 (17), pp. 3610-3618
Kingsley, D. M., The TGF-beta superfamily: New members, new receptors, and new genetic tests of function in different organisms (1994) Genes Dev, 8 (2), pp. 133-146
Harrison, C. A., Gray, P. C., Koerber, S. C., Fischer, W., Vale, W., Identification of a functional binding site for activin on the type I receptor ALK4 (2003) J. Biol. Chem, 278 (23), pp. 21129-21135
Innis, C. A., Shi, J., Blundell, T. L., Evolutionary trace analysis of TGF-beta and related growth factors: Implications for site-directed mutagenesis (2000) Protein Eng, 13 (12), pp. 839-847
Sternberg, M. J., Gabb, H. A., Jackson, R. M., Moont, G., Protein-protein docking. Generation and filtering of complexes (2000) Methods Mol. Biol, 143, pp. 399-415
Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor
The protein Cripto is the founding member of the extra-cellular EGF-CFC growth factors, which are composed of two adjacent cysteine-rich domains: the EGF-like and the CFC. Members of the EGF-CFC family play key roles in embryonic development and are also implicated in tumourigenesis. Cripto is highly over-expressed in many tumours, while it is poorly detectable in normal tissues. Although both Cripto domains are involved in its tumourigenic activity, the CFC domain appears to play a crucial role. Indeed, through this domain, Cripto interferes with the onco-suppressive activity of Activins, either by blocking the Activin receptor ALK4 or by antagonising proteins of the TGF-beta family. We have undertaken the chemical synthesis and the structural characterisation of human CFC Cripto domain. Using a combined NMR and computational approach, supported by binding studies by SPR, we have investigated the molecular basis of the interaction between h-CFC and ALK4. Binding studies indicate that the synthetic h-CFC interacts with the ALK4 receptor with a K(D) in micro M range, whereas it does not recognise the ActRIIB receptor. The NMR study shows that the h-CFC overall topology is determined by the presence of three disulfide bridges and that residues H120 and W124 are located between the first strand and the first loop with the side chains externally exposed. A model of the CFC-ALK4 complex has also been obtained by molecular docking and shows that all residues indicated by prior mutagenesis studies can contribute to the ALK4-CFC interaction at the protein-protein interface.
Structural insights into the interaction between the Cripto CFC domain and the ALK4 receptor