- Email: [email protected]
WW Domains in the Heart of Smad Regulation
Structure
Previews REFERENCES
C.J., Minor, W., and Herr, J.C. (2008). Endocrinology 149, 2108–2120.
Bateman, A., Coggill, P., and Finn, R.D. (2010). Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66, 1148–1152.
Lespinet, O., and Labedan, B. (2005). Science 307, 42.
Chen, L., and Vitkup, D. (2007). Trends Biotechnol. 25, 343–348.
le Maire, A., Gelin, M., Pochet, S., Hoh, F., Pirocchi, M., Guichou, J.-F., Ferrer, J.L., and Labesse, G. (2011). Acta Crystallogr. D Biol. Crystallogr. 67, 747–755.
Hajduk, P.J., and Greer, J. (2007). Nat. Rev. Drug Discov. 6, 211–219. Jha, K.N., Shumilin, I.A., Digilio, L.C., Chertihin, O., Zheng, H., Schmitz, G., Visconti, P.E., Flickinger,
Punta, M., Coggill, P.C., Eberhardt, R.Y., Mistry, J., Tate, J., Boursnell, C., Pang, N., Forslund, K., Ceric, G., Clements, J., et al. (2012). Nucleic Acids Res. 40 (Database issue), D290–D301.
Shumilin, I.A., Cymborowski, M., Chertihin, O., Jha, K.N., Herr, J.C., Lesley, S.A., Joachimiak, A., and Minor, W. (2012). Structure 20, this issue, 1715–1725. Vedadi, M., Niesen, F.H., Allali-Hassani, A., Fedorov, O.Y., Finerty, P.J., Jr., Wasney, G.A., Yeung, R., Arrowsmith, C., Ball, L.J., Berglund, H., et al. (2006). Proc. Natl. Acad. Sci. USA 103, 15835–15840. Zhang, R.G., Grembecka, J., Vinokour, E., Collart, F., Dementieva, I., Minor, W., and Joachimiak, A. (2002). J. Struct. Biol. 139, 161–170.
WW Domains in the Heart of Smad Regulation Marius Sudol1,2,* 1Weis
Center for Research, Geisinger Clinic, 100 North Academy Avenue, Danville, PA 17821, USA of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.str.2012.09.007 2Department
WW domains are small modules that mediate protein/protein interactions. In this issue of Structure, Arago´n and colleagues show that a WW domain of YAP can mediate complexes with either the canonical PY motif in an inhibitory Smad or engage in phosphorylation-dependent complexes with one of the activated Smads. The propensity of YAP WW to recognize a pSP motif is a surprising find with a number of far-reaching ramifications. Modular protein domains are basic units of the canonical code of cellular signaling. The paradigm-changing discovery of modular protein domains, exemplified by the characterization of the Src homology (SH2) domain as a snippet of a protein, rather than a large surface that is complementary to the cognate ligand protein (Pawson, 1988), changed our view of how protein complexes are formed, regulated, and elicit discrete signals. In this issue of Structure, Arago´n et al. (2012) provide an elegant description of the versatility of one of the smallest modular protein domains, known as the WW domain (Bork and Sudol, 1994). By studying signaling events orchestrated by transforming growth factor-b and bone morphogenic protein pathways, the authors revealed a surprising plasticity of WW domain-containing proteins in assembling signaling complexes. Two modes of functional interaction between Smads and its WW domain-containing regulators, including a transcriptional coactivator, YAP, and E3 ubiquitin ligases,
such as Nedd4L and Smurf1/2 were characterized in detail. The authors used a fine combination of structural biology to characterize the protein complexes at high resolution and molecular analyses in cell culture models to interrogate the function of the signaling complexes. One mode of WW domain-mediated interactions was shown for the inhibitory Smad (Smad7) as a constitutive and phosphorylation-independent event. The first WW domain of YAP isoform,YAP1-2, was shown to mediate a complex with the PY motif, also known as PPxY motif, of Smad7. The other mode of interaction was shown with Smad1, one of the receptor regulated Smads, as a phosphorylation-dependent and composite complex in which both WW domains of YAP were involved in unison, recognizing two sequence motifs within Smad1 (Arago´n et al., 2011). More precisely, in the interaction with Smad1, the first WW domain of YAP was engaged in binding to the phosphorylated serine-proline motif (serine 206 in human Smad1). The
second WW domain of YAP formed a canonical complex with the adjacent PY motif of Smad1. The propensity of YAP WW1 domain to recognize the pSP motif was a surprising find (Chen and Sudol, 1995). Interestingly, the authors determined that the affinity of the YAP-WW1WW2 for the composite pSP-PY site of Smad1 was eight times higher than that of the YAP-WW1 for Smad7, suggesting a competitive interaction that is balanced by high local concentrations of Smad7 in the cell nucleus. The plasticity of the first WW domain of YAP in being able to recognize either canonical PY motif or the phosphorylated motif, pSP, is appreciated as a novel finding with important ramifications. Before the reports of Arago´n and colleagues, WW domain interactions with pSP or pTP motifs were limited to Pin1 WW domain and to a handful of WW domains of Pin1-related proteins (Lu et al., 1999). The unique mode of recognition of phosphorylated motifs by Pin1 was reinforced by the structure of
Structure 20, October 10, 2012 ª2012 Elsevier Ltd All rights reserved 1619
Structure
Previews
University in New York City where the SH3 domain and its proline-rich ligand were characterized by the Hanafusa and Baltimore laboratories (reviewed in Sudol, 2011). Curiously, SH3 and WW domains are functionally related by their ability to recognize proline-rich or proline-containing ligands. Acknowledging the large diversity of canonical and non-canonical ligands currently known for SH3 domains (reviewed by Saksela and Permi, 2012), we are confident that the actual repertoire of WW domain ligands and the plasticity by which the WW module forms complexes with them is quite vast. For sure, new surprises are in store! Figure 1. Different Modes by which WW Domains Form Complexes with Cognate Proteins The WW domain-mediated complexes discussed by Arago´n and colleagues are shown in color. Other modes by which WW domain complexes are formed and regulated (see Sudol, 2010 for details) are shown in black, white, and gray.
Pin1 complex with the phosphorylated peptide (where the ligand-binding pocket is not intrinsic to the WW domain alone but is formed by both), the WW domain of Pin1, and the enzymatic domain of iso-prolyl iomerase (Verdecia et al., 2000). The fact that the WW domain of so-called Class I WW domains, which mainly recognize PY motifs, has an ability to recognize and bind pSP motifs, suggests that other WW domains (circa 100 domains in the human proteome) may have such a propensity as well. The second important ramification of the two reports by Arago´n and colleagues is that the YAP oncogene is one of the two main effectors of the newly delineated and intensely studied Hippo tumor suppressor pathway (Sudol, 2010). The other effector is TAZ, an ortholog of YAP, which has a single WW domain
(with the exception of fish TAZ). Since both YAP and TAZ are controlled by a cassette of upstream serine and threonine kinases such as MST and LATS kinases, it is likely that new regulatory complexes of YAP/TAZ with other proteins exist within the Hippo network because of the ability of YAP (perhaps TAZ as well) WW domains to sense selected pS/TP motifs as phosphoswitches (Sudol and Harvey, 2010). Arago´n and colleagues also reminded us that WW domains have the ability to dimerize as hetero-dimers confirming previous reports on this feature in the signaling ability of WW domains (reviewed in Sudol, 2010) (Figure 1). Coincidentally, the WW domain as a modular protein domain that interacts with proline-rich ligands was identified in the same building at The Rockefeller
1620 Structure 20, October 10, 2012 ª2012 Elsevier Ltd All rights reserved
REFERENCES Arago´n, E., Goerner, N., Zaromytidou, A.I., Xi, Q., Escobedo, A., Massague´, J., and Macias, M.J. (2011). Genes Dev. 25, 1275–1288. Arago´n, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massague´,, J., and Macias, M.J. (2012). Structure 20, this issue, 1726–1736. Bork, P., and Sudol, M. (1994). Trends Biochem. Sci. 19, 531–533. Chen, H.I., and Sudol, M. (1995). Proc. Natl. Acad. Sci. USA 92, 7819–7823. Lu, P.J., Zhou, X.Z., Shen, M., and Lu, K.P. (1999). Science 283, 1325–1328. Pawson, T. (1988). Oncogene 3, 491–495. Saksela, K., and Permi, P. (2012). FEBS Lett. 586, 2609–2614. Sudol, M. (2010). Genes Cancer 1, 1115–1118. Sudol, M. (2011). Oncogene 30, 3003–3010. Sudol, M., and Harvey, K.F. (2010). Trends Biochem. Sci. 35, 627–633. Verdecia, M.A., Bowman, M.E., Lu, K.P., Hunter, T., and Noel, J.P. (2000). Nat. Struct. Biol. 7, 639–643.
Previews REFERENCES
C.J., Minor, W., and Herr, J.C. (2008). Endocrinology 149, 2108–2120.
Bateman, A., Coggill, P., and Finn, R.D. (2010). Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 66, 1148–1152.
Lespinet, O., and Labedan, B. (2005). Science 307, 42.
Chen, L., and Vitkup, D. (2007). Trends Biotechnol. 25, 343–348.
le Maire, A., Gelin, M., Pochet, S., Hoh, F., Pirocchi, M., Guichou, J.-F., Ferrer, J.L., and Labesse, G. (2011). Acta Crystallogr. D Biol. Crystallogr. 67, 747–755.
Hajduk, P.J., and Greer, J. (2007). Nat. Rev. Drug Discov. 6, 211–219. Jha, K.N., Shumilin, I.A., Digilio, L.C., Chertihin, O., Zheng, H., Schmitz, G., Visconti, P.E., Flickinger,
Punta, M., Coggill, P.C., Eberhardt, R.Y., Mistry, J., Tate, J., Boursnell, C., Pang, N., Forslund, K., Ceric, G., Clements, J., et al. (2012). Nucleic Acids Res. 40 (Database issue), D290–D301.
Shumilin, I.A., Cymborowski, M., Chertihin, O., Jha, K.N., Herr, J.C., Lesley, S.A., Joachimiak, A., and Minor, W. (2012). Structure 20, this issue, 1715–1725. Vedadi, M., Niesen, F.H., Allali-Hassani, A., Fedorov, O.Y., Finerty, P.J., Jr., Wasney, G.A., Yeung, R., Arrowsmith, C., Ball, L.J., Berglund, H., et al. (2006). Proc. Natl. Acad. Sci. USA 103, 15835–15840. Zhang, R.G., Grembecka, J., Vinokour, E., Collart, F., Dementieva, I., Minor, W., and Joachimiak, A. (2002). J. Struct. Biol. 139, 161–170.
WW Domains in the Heart of Smad Regulation Marius Sudol1,2,* 1Weis
Center for Research, Geisinger Clinic, 100 North Academy Avenue, Danville, PA 17821, USA of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.str.2012.09.007 2Department
WW domains are small modules that mediate protein/protein interactions. In this issue of Structure, Arago´n and colleagues show that a WW domain of YAP can mediate complexes with either the canonical PY motif in an inhibitory Smad or engage in phosphorylation-dependent complexes with one of the activated Smads. The propensity of YAP WW to recognize a pSP motif is a surprising find with a number of far-reaching ramifications. Modular protein domains are basic units of the canonical code of cellular signaling. The paradigm-changing discovery of modular protein domains, exemplified by the characterization of the Src homology (SH2) domain as a snippet of a protein, rather than a large surface that is complementary to the cognate ligand protein (Pawson, 1988), changed our view of how protein complexes are formed, regulated, and elicit discrete signals. In this issue of Structure, Arago´n et al. (2012) provide an elegant description of the versatility of one of the smallest modular protein domains, known as the WW domain (Bork and Sudol, 1994). By studying signaling events orchestrated by transforming growth factor-b and bone morphogenic protein pathways, the authors revealed a surprising plasticity of WW domain-containing proteins in assembling signaling complexes. Two modes of functional interaction between Smads and its WW domain-containing regulators, including a transcriptional coactivator, YAP, and E3 ubiquitin ligases,
such as Nedd4L and Smurf1/2 were characterized in detail. The authors used a fine combination of structural biology to characterize the protein complexes at high resolution and molecular analyses in cell culture models to interrogate the function of the signaling complexes. One mode of WW domain-mediated interactions was shown for the inhibitory Smad (Smad7) as a constitutive and phosphorylation-independent event. The first WW domain of YAP isoform,YAP1-2, was shown to mediate a complex with the PY motif, also known as PPxY motif, of Smad7. The other mode of interaction was shown with Smad1, one of the receptor regulated Smads, as a phosphorylation-dependent and composite complex in which both WW domains of YAP were involved in unison, recognizing two sequence motifs within Smad1 (Arago´n et al., 2011). More precisely, in the interaction with Smad1, the first WW domain of YAP was engaged in binding to the phosphorylated serine-proline motif (serine 206 in human Smad1). The
second WW domain of YAP formed a canonical complex with the adjacent PY motif of Smad1. The propensity of YAP WW1 domain to recognize the pSP motif was a surprising find (Chen and Sudol, 1995). Interestingly, the authors determined that the affinity of the YAP-WW1WW2 for the composite pSP-PY site of Smad1 was eight times higher than that of the YAP-WW1 for Smad7, suggesting a competitive interaction that is balanced by high local concentrations of Smad7 in the cell nucleus. The plasticity of the first WW domain of YAP in being able to recognize either canonical PY motif or the phosphorylated motif, pSP, is appreciated as a novel finding with important ramifications. Before the reports of Arago´n and colleagues, WW domain interactions with pSP or pTP motifs were limited to Pin1 WW domain and to a handful of WW domains of Pin1-related proteins (Lu et al., 1999). The unique mode of recognition of phosphorylated motifs by Pin1 was reinforced by the structure of
Structure 20, October 10, 2012 ª2012 Elsevier Ltd All rights reserved 1619
Structure
Previews
University in New York City where the SH3 domain and its proline-rich ligand were characterized by the Hanafusa and Baltimore laboratories (reviewed in Sudol, 2011). Curiously, SH3 and WW domains are functionally related by their ability to recognize proline-rich or proline-containing ligands. Acknowledging the large diversity of canonical and non-canonical ligands currently known for SH3 domains (reviewed by Saksela and Permi, 2012), we are confident that the actual repertoire of WW domain ligands and the plasticity by which the WW module forms complexes with them is quite vast. For sure, new surprises are in store! Figure 1. Different Modes by which WW Domains Form Complexes with Cognate Proteins The WW domain-mediated complexes discussed by Arago´n and colleagues are shown in color. Other modes by which WW domain complexes are formed and regulated (see Sudol, 2010 for details) are shown in black, white, and gray.
Pin1 complex with the phosphorylated peptide (where the ligand-binding pocket is not intrinsic to the WW domain alone but is formed by both), the WW domain of Pin1, and the enzymatic domain of iso-prolyl iomerase (Verdecia et al., 2000). The fact that the WW domain of so-called Class I WW domains, which mainly recognize PY motifs, has an ability to recognize and bind pSP motifs, suggests that other WW domains (circa 100 domains in the human proteome) may have such a propensity as well. The second important ramification of the two reports by Arago´n and colleagues is that the YAP oncogene is one of the two main effectors of the newly delineated and intensely studied Hippo tumor suppressor pathway (Sudol, 2010). The other effector is TAZ, an ortholog of YAP, which has a single WW domain
(with the exception of fish TAZ). Since both YAP and TAZ are controlled by a cassette of upstream serine and threonine kinases such as MST and LATS kinases, it is likely that new regulatory complexes of YAP/TAZ with other proteins exist within the Hippo network because of the ability of YAP (perhaps TAZ as well) WW domains to sense selected pS/TP motifs as phosphoswitches (Sudol and Harvey, 2010). Arago´n and colleagues also reminded us that WW domains have the ability to dimerize as hetero-dimers confirming previous reports on this feature in the signaling ability of WW domains (reviewed in Sudol, 2010) (Figure 1). Coincidentally, the WW domain as a modular protein domain that interacts with proline-rich ligands was identified in the same building at The Rockefeller
1620 Structure 20, October 10, 2012 ª2012 Elsevier Ltd All rights reserved
REFERENCES Arago´n, E., Goerner, N., Zaromytidou, A.I., Xi, Q., Escobedo, A., Massague´, J., and Macias, M.J. (2011). Genes Dev. 25, 1275–1288. Arago´n, E., Goerner, N., Xi, Q., Gomes, T., Gao, S., Massague´,, J., and Macias, M.J. (2012). Structure 20, this issue, 1726–1736. Bork, P., and Sudol, M. (1994). Trends Biochem. Sci. 19, 531–533. Chen, H.I., and Sudol, M. (1995). Proc. Natl. Acad. Sci. USA 92, 7819–7823. Lu, P.J., Zhou, X.Z., Shen, M., and Lu, K.P. (1999). Science 283, 1325–1328. Pawson, T. (1988). Oncogene 3, 491–495. Saksela, K., and Permi, P. (2012). FEBS Lett. 586, 2609–2614. Sudol, M. (2010). Genes Cancer 1, 1115–1118. Sudol, M. (2011). Oncogene 30, 3003–3010. Sudol, M., and Harvey, K.F. (2010). Trends Biochem. Sci. 35, 627–633. Verdecia, M.A., Bowman, M.E., Lu, K.P., Hunter, T., and Noel, J.P. (2000). Nat. Struct. Biol. 7, 639–643.