-
[show abstract]
[hide abstract]
ABSTRACT: Transforming growth factor (TGF)-β and BMP signaling is mediated by Smads 1-5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-β and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators bind PY motifs and adjacent CDK/MAPK and GSK3 phosphorylation sites in R-Smads in a selective and regulated manner. In contrast, here we show that Smad7 binds YAP, Smurf1, Smurf2, and Nedd4L constitutively, the binding involving a PY motif in Smad7 and no phosphorylation. We also provide a structural basis for how regulators that use WW domain pairs for selective interactions with R-Smads, resort to one single versatile WW domain for binding Smad7 to centralize regulation in the TGF-β and BMP pathways.
Structure 08/2012; 20(10):1726-36. · 6.35 Impact Factor
-
Pablo Martín-Gago,
Marc Gomez-Caminals,
Rosario Ramón,
Xavier Verdaguer,
Pau Martin-Malpartida, Eric Aragón,
Jimena Fernández-Carneado,
Berta Ponsati,
Pilar López-Ruiz,
Maria Alicia Cortes,
Begoña Colás,
Maria J Macias,
Antoni Riera
[show abstract]
[hide abstract]
ABSTRACT: The π-π aromatic interactions between amino acids 6, 7, and 11 in the natural hormone somatostatin are crucial for conformational stability. In their Communication on page 1820 ff., M. J. Macias, A. Riera, and co-workers describe that peptidic analogues obtained by replacing each phenylalanine with mesitylalanine are conformationally more rigid than the parent hormone. This strategy has yielded the first 3D structures of 14-amino-acid somatostatin analogues.
Angewandte Chemie International Edition 02/2012; 51(8):1977. · 13.45 Impact Factor
-
Pablo Martín-Gago,
Marc Gomez-Caminals,
Rosario Ramón,
Xavier Verdaguer,
Pau Martin-Malpartida, Eric Aragón,
Jimena Fernández-Carneado,
Berta Ponsati,
Pilar López-Ruiz,
Maria Alicia Cortes,
Begoña Colás,
Maria J Macias,
Antoni Riera
[show abstract]
[hide abstract]
ABSTRACT: Going through the motions: Somatostatin analogues having greater conformational rigidity than somatostatin have been prepared by substituting Phe residues in the native sequence with mesityl alanine (Msa; see structure). The analogues show high affinity for SSTR receptors, thus showing that fine-tuning of noncovalent interactions between amino acid side chains can modulate peptide affinity and selectivity.
Angewandte Chemie International Edition 12/2011; 51(8):1820-5. · 13.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: When directed to the nucleus by TGF-β or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-β pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-β signal delivery to turnover of the Smad signal transducers.
Genes & development 06/2011; 25(12):1275-88. · 12.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Fast 2D NMR-based screening can be achieved using Hadamard encoded spectroscopy to focus on the signals of interest (e.g., enzyme active or ligand recognition sites). By recording a set of Hadamard spectra (a "Hadamard constellation") with relative offsets comparable to the excitation bandwidth, quantitative ligand-induced shifts can be obtained from peak intensities.
Journal of the American Chemical Society 07/2006; 128(22):7146-7. · 9.91 Impact Factor
