Protein Engineering, Vol. 13, No. 12, 839-847,
December 2000
© 2000 Oxford University Press
Evolutionary trace analysis of TGF-ß and related growth factors: implications for site-directed mutagenesis
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK
The TGF-ß family of growth factors contains a large number of homologous proteins, grouped in several subfamilies on the basis of sequence identity. These subgroups can be combined into three broader groups of related cytokines, with marked specificities for their cellular receptors: the TGF-ßs, the activins and the BMPs/GDFs. Although structural information is available for some members of the TGF-ß family, very little is known about the way in which these growth factors interact with the extra-cellular domains of their multiple cell surface receptors or with the specific protein inhibitors thought to modulate their activity. In this paper, we use the evolutionary trace method [Lichtarge et al. (1996) J. Mol. Biol., 257, 342–358] to locate two functional patches on the surface of TGF-ß-like growth factors. The first of these is centred on a conserved proline (P36 in TGF-ßs 1–3) and contains two amino acids which could account for the receptor specificity of TGF-ßs (H34 and E35). The second patch is located on the other side of the growth factor protomer and surrounds a hydrophobic cavity, large enough to accommodate the side chain of an aromatic residue. In addition to two conserved tryptophans at positions 30 and 32, the main protagonists in this potential binding interface are found at positions 31, 92, 93 and 98. Several mutagenesis studies have highlighted the importance of the C-terminal region of the growth factor molecule in TGF-ßs and of residues in activin A equivalent to positions 31 and 94 of the TGF-ßs for the binding of type II receptors to these ligands. These data, together with our improved knowledge of possible functional residues, can be used in future structure–function analysis experiments.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. S. Negi, C. H. Schein, N. Oezguen, T. D. Power, and W. Braun InterProSurf: a web server for predicting interacting sites on protein surfaces Bioinformatics, December 15, 2007; 23(24): 3397 - 3399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S J. Lin, T. F Lerch, R. W Cook, T. S Jardetzky, and T. K Woodruff The structural basis of TGF-{beta}, bone morphogenetic protein, and activin ligand binding. Reproduction, August 1, 2006; 132(2): 179 - 190. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Mihalek, I. Res, and O. Lichtarge Evolutionary trace report_maker: a new type of service for comparative analysis of proteins Bioinformatics, July 1, 2006; 22(13): 1656 - 1657. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Kristensen, B. Y. Chen, V. Y. Fofanov, R. M. Ward, A. M. Lisewski, M. Kimmel, L. E. Kavraki, and O. Lichtarge Recurrent use of evolutionary importance for functional annotation of proteins based on local structural similarity Protein Sci., June 1, 2006; 15(6): 1530 - 1536. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R. Bowman, R. L. Welschhans, H. Jayaram, N. D. Stow, V. G. Preston, and F. A. Quiocho Structural Characterization of the UL25 DNA-Packaging Protein from Herpes Simplex Virus Type 1 J. Virol., March 1, 2006; 80(5): 2309 - 2317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pei, W. Cai, L. N. Kinch, and N. V. Grishin Prediction of functional specificity determinants from protein sequences using log-likelihood ratios Bioinformatics, January 15, 2006; 22(2): 164 - 171. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Cook, T. B. Thompson, S. P. Kurup, T. S. Jardetzky, and T. K. Woodruff Structural Basis for a Functional Antagonist in the Transforming Growth Factor {beta} Superfamily J. Biol. Chem., December 2, 2005; 280(48): 40177 - 40186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Donald and E. I. Shakhnovich Predicting specificity-determining residues in two large eukaryotic transcription factor families Nucleic Acids Res., August 5, 2005; 33(14): 4455 - 4465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Landau, I. Mayrose, Y. Rosenberg, F. Glaser, E. Martz, T. Pupko, and N. Ben-Tal ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures Nucleic Acids Res., July 1, 2005; 33(suppl_2): W299 - W302. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Saito, T. Oyama, and T. Shirai Detection of subunit interfacial modifications by tracing the evolution of clamp-loader complex Protein Eng. Des. Sel., March 1, 2005; 18(3): 139 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chakravarty, A. M. Hutson, M. K. Estes, and B. V. V. Prasad Evolutionary Trace Residues in Noroviruses: Importance in Receptor Binding, Antigenicity, Virion Assembly, and Strain Diversity J. Virol., January 1, 2005; 79(1): 554 - 568. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. O'Leary, J. M. Hamilton, C. M. Deane, N. V. Valeyev, L. J. Sandell, and A. K. Downing Solution Structure and Dynamics of a Prototypical Chordin-like Cysteine-rich Repeat (von Willebrand Factor Type C Module) from Collagen IIA J. Biol. Chem., December 17, 2004; 279(51): 53857 - 53866. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. ZHU and J. TYTGAT Evolutionary epitopes of Hsp90 and p23: implications for their interaction FASEB J, June 1, 2004; 18(9): 940 - 947. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Madabushi, A. K. Gross, A. Philippi, E. C. Meng, T. G. Wensel, and O. Lichtarge Evolutionary Trace of G Protein-coupled Receptors Reveals Clusters of Residues That Determine Global and Class-specific Functions J. Biol. Chem., February 27, 2004; 279(9): 8126 - 8132. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. A. Stebbings and K. Mizuguchi HOMSTRAD: recent developments of the Homologous Protein Structure Alignment Database Nucleic Acids Res., January 1, 2004; 32(90001): D203 - 207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G.-i. Lee, Z. Ding, J. C. Walker, and S. R. Van Doren NMR structure of the forkhead-associated domain from the Arabidopsis receptor kinase-associated protein phosphatase PNAS, September 30, 2003; 100(20): 11261 - 11266. [Abstract] [Full Text] [PDF]
|
|