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PDBsum entry 1dev

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protein Protein-protein interface(s) links
Signaling protein PDB id
1dev
Jmol PyMol
Contents
Protein chains
194 a.a. *
41 a.a. *
39 a.a. *
* Residue conservation analysis
PDB id:
1dev
Name: Signaling protein
Title: Crystal structure of smad2 mh2 domain bound to the smad- binding domain of sara
Structure: Mad (mothers against decapentaplegic, drosophila) homolog 2. Chain: a, c. Fragment: smad2 mh2 domain. Engineered: yes. Smad anchor for receptor activation. Chain: b, d. Fragment: sara smad2-binding domain. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Other_details: this sequence occurs naturally in humans. Other_details: this sequence occurs naturally in humans
Biol. unit: Dimer (from PQS)
Resolution:
2.20Å     R-factor:   0.218     R-free:   0.276
Authors: Y.Shi,G.Wu
Key ref:
G.Wu et al. (2000). Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 287, 92-97. PubMed id: 10615055 DOI: 10.1126/science.287.5450.92
Date:
15-Nov-99     Release date:   21-Jan-00    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q15796  (SMAD2_HUMAN) -  Mothers against decapentaplegic homolog 2
Seq:
Struc:
467 a.a.
194 a.a.
Protein chain
Pfam   ArchSchema ?
O95405  (ZFYV9_HUMAN) -  Zinc finger FYVE domain-containing protein 9
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1425 a.a.
41 a.a.
Protein chain
Pfam   ArchSchema ?
O95405  (ZFYV9_HUMAN) -  Zinc finger FYVE domain-containing protein 9
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
1425 a.a.
39 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     intracellular   1 term 
  Biological process     regulation of transcription, DNA-dependent   1 term 

 

 
DOI no: 10.1126/science.287.5450.92 Science 287:92-97 (2000)
PubMed id: 10615055  
 
 
Structural basis of Smad2 recognition by the Smad anchor for receptor activation.
G.Wu, Y.G.Chen, B.Ozdamar, C.A.Gyuricza, P.A.Chong, J.L.Wrana, J.Massagué, Y.Shi.
 
  ABSTRACT  
 
The Smad proteins mediate transforming growth factor-beta (TGFbeta) signaling from the transmembrane serine-threonine receptor kinases to the nucleus. The Smad anchor for receptor activation (SARA) recruits Smad2 to the TGFbeta receptors for phosphorylation. The crystal structure of a Smad2 MH2 domain in complex with the Smad-binding domain (SBD) of SARA has been determined at 2.2 angstrom resolution. SARA SBD, in an extended conformation comprising a rigid coil, an alpha helix, and a beta strand, interacts with the beta sheet and the three-helix bundle of Smad2. Recognition between the SARA rigid coil and the Smad2 beta sheet is essential for specificity, whereas interactions between the SARA beta strand and the Smad2 three-helix bundle contribute significantly to binding affinity. Comparison of the structures between Smad2 and a comediator Smad suggests a model for how receptor-regulated Smads are recognized by the type I receptors.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Overall structure of the Smad2 MH2 domain in complex with a SARA SBD. (A) The schematic representation on the right panel is related to the one on the left by a 90° rotation along the horizontal axis. Smad2 and SARA are shown in green and pink, respectively. The secondary structural elements in SARA and some prominent features in Smad2 are labeled and color-coded. (B) Sequence of the SARA SBD showing its secondary structural elements. The bar graph below sequence shows the buried surface area per SARA residue upon complex formation. The residues that are targeted by inactivating mutations are highlighted in red (Fig. 1C). (C) Superimposition of the structures of the MH2 domains in Smad2 (green) and Smad4 (red), shown in stereo view. The disordered loop between helices H3 and H4 in Smad4 is indicated by a red dotted line. This figure was prepared with MOLSCRIPT (24).
Figure 3.
Fig. 3. Schematic representation of the interactions between Smad2 and SARA. (A) The interactions are predominantly hydrophobic in nature. The surface of Smad2 MH2 domain is represented by degrees of hydrophobicity. The C backbone of SARA SBD is shown in pink and the buried hydrophobic residues are highlighted in orange. This figure was prepared with GRASP (25). (B) A closeup view of the interactions between the rigid coil of SARA and the strands B8 and B9 of Smad2. Smad2 and SARA are colored green and pink, respectively. The interacting side chains are shown in yellow for Smad2 and in purple for SARA. The O and N atoms are shown as red and blue balls, respectively. The left panel shows the interface, whereas the right panel shows the conformation of the rigid coil by itself. Aside from extensive van der Waals interactions at the interface, there are a total of five intermolecular H bonds. These include: Ser671 O to Tyr366 carbonyl, Pro672 carbonyl to Trp368 N 1, Tyr680 O to Lys375 amide, Ser682 amide to Asn381 carbonyl, and Ser682 carbonyl to Asn381 amide. (C) A closeup view of the interactions between the helix of SARA and strands B5 and B6 of Smad2. Color coding scheme is identical to (B). (D) A closeup view of the interactions between the strand of SARA and the three-helix bundle and strand B1' of Smad2.
 
  The above figures are reprinted by permission from the AAAs: Science (2000, 287, 92-97) copyright 2000.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21266541 C.Huang, R.Du, P.Zhang, H.Meng, H.Jia, Y.Song, M.Li, Y.Zhang, and S.Sun (2011).
Expression, purification, and functional characterization of recombinant PTD-SARA.
  Acta Biochim Biophys Sin (Shanghai), 43, 110-117.  
19762341 K.Miyazono, Y.Kamiya, and M.Morikawa (2010).
Bone morphogenetic protein receptors and signal transduction.
  J Biochem, 147, 35-51.  
20890540 L.Li, B.P.Orner, T.Huang, A.P.Hinck, and L.L.Kiessling (2010).
Peptide ligands that use a novel binding site to target both TGF-β receptors.
  Mol Biosyst, 6, 2392-2402.  
20129061 Y.Watanabe, S.Itoh, T.Goto, E.Ohnishi, M.Inamitsu, F.Itoh, K.Satoh, E.Wiercinska, W.Yang, L.Shi, A.Tanaka, N.Nakano, A.M.Mommaas, H.Shibuya, P.Ten Dijke, and M.Kato (2010).
TMEPAI, a transmembrane TGF-beta-inducible protein, sequesters Smad proteins from active participation in TGF-beta signaling.
  Mol Cell, 37, 123-134.  
19620243 C.E.Runyan, T.Hayashida, S.Hubchak, J.F.Curley, and H.W.Schnaper (2009).
Role of SARA (SMAD anchor for receptor activation) in maintenance of epithelial cell phenotype.
  J Biol Chem, 284, 25181-25189.  
19557331 C.Wang, L.Chen, L.Wang, and J.Wu (2009).
Crystal structure of the MH2 domain of Drosophila Mad.
  Sci China C Life Sci, 52, 539-544.
PDB code: 3gmj
19538713 K.Tsuchida, M.Nakatani, K.Hitachi, A.Uezumi, Y.Sunada, H.Ageta, and K.Inokuchi (2009).
Activin signaling as an emerging target for therapeutic interventions.
  Cell Commun Signal, 7, 15.  
19260013 P.Tompa, M.Fuxreiter, C.J.Oldfield, I.Simon, A.K.Dunker, and V.N.Uversky (2009).
Close encounters of the third kind: disordered domains and the interactions of proteins.
  Bioessays, 31, 328-335.  
19917253 S.Gao, C.Alarcón, G.Sapkota, S.Rahman, P.Y.Chen, N.Goerner, M.J.Macias, H.Erdjument-Bromage, P.Tempst, and J.Massagué (2009).
Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling.
  Mol Cell, 36, 457-468.  
19556242 S.I.Kim, J.H.Kwak, H.J.Na, J.K.Kim, Y.Ding, and M.E.Choi (2009).
Transforming growth factor-beta (TGF-beta1) activates TAK1 via TAB1-mediated autophosphorylation, independent of TGF-beta receptor kinase activity in mesangial cells.
  J Biol Chem, 284, 22285-22296.  
  18997322 R.Hao, L.Chen, J.W.Wu, and Z.X.Wang (2008).
Structure of Drosophila Mad MH2 domain.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 64, 986-990.
PDB code: 3dit
18175316 R.Hariharan, and M.R.Pillai (2008).
Structure-function relationship of inhibitory Smads: Structural flexibility contributes to functional divergence.
  Proteins, 71, 1853-1862.  
18061509 S.Ross, and C.S.Hill (2008).
How the Smads regulate transcription.
  Int J Biochem Cell Biol, 40, 383-408.  
18753140 T.Mori, K.Kitano, S.Terawaki, R.Maesaki, Y.Fukami, and T.Hakoshima (2008).
Structural basis for CD44 recognition by ERM proteins.
  J Biol Chem, 283, 29602-29612.
PDB code: 2zpy
17591701 F.Dai, C.Chang, X.Lin, P.Dai, L.Mei, and X.H.Feng (2007).
Erbin inhibits transforming growth factor beta signaling through a novel Smad-interacting domain.
  Mol Cell Biol, 27, 6183-6194.  
17907120 M.E.Hahn, J.P.Pellois, M.Vila-Perelló, and T.W.Muir (2007).
Tunable photoactivation of a post-translationally modified signaling protein and its unmodified counterpart in live cells.
  Chembiochem, 8, 2100-2105.  
17643432 P.T.Loverde, A.Osman, and A.Hinck (2007).
Schistosoma mansoni: TGF-beta signaling pathways.
  Exp Parasitol, 117, 304-317.  
16449645 A.Kurisaki, K.Kurisaki, M.Kowanetz, H.Sugino, Y.Yoneda, C.H.Heldin, and A.Moustakas (2006).
The mechanism of nuclear export of Smad3 involves exportin 4 and Ran.
  Mol Cell Biol, 26, 1318-1332.  
16775010 B.M.Zhao, and F.M.Hoffmann (2006).
Inhibition of transforming growth factor-beta1-induced signaling and epithelial-to-mesenchymal transition by the Smad-binding peptide aptamer Trx-SARA.
  Mol Biol Cell, 17, 3819-3831.  
16828554 H.Remaut, and G.Waksman (2006).
Protein-protein interaction through beta-strand addition.
  Trends Biochem Sci, 31, 436-444.  
15879500 S.A.Abdalla, and M.Letarte (2006).
Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease.
  J Med Genet, 43, 97.  
17130172 W.Pirovano, K.A.Feenstra, and J.Heringa (2006).
Sequence comparison by sequence harmony identifies subtype-specific functional sites.
  Nucleic Acids Res, 34, 6540-6548.  
16154084 B.Y.Qin, C.Liu, H.Srinath, S.S.Lam, J.J.Correia, R.Derynck, and K.Lin (2005).
Crystal structure of IRF-3 in complex with CBP.
  Structure, 13, 1269-1277.  
16010672 D.LaGamba, A.Nawshad, and E.D.Hay (2005).
Microarray analysis of gene expression during epithelial-mesenchymal transformation.
  Dev Dyn, 234, 132-142.  
15750622 Q.Cui, S.K.Lim, B.Zhao, and F.M.Hoffmann (2005).
Selective inhibition of TGF-beta responsive genes by Smad-interacting peptide aptamers from FoxH1, Lef1 and CBP.
  Oncogene, 24, 3864-3874.  
16212511 X.H.Feng, and R.Derynck (2005).
Specificity and versatility in tgf-beta signaling through Smads.
  Annu Rev Cell Dev Biol, 21, 659-693.  
15614040 Y.Matsuzaki, S.Hashimoto, T.Fujita, T.Suzuki, T.Sakurai, K.Matsushima, and Y.Kawakami (2005).
Systematic identification of human melanoma antigens using serial analysis of gene expression (SAGE).
  J Immunother (1997), 28, 10-19.  
15356616 C.Le Roy, and J.L.Wrana (2004).
Cell biology: an unexpected social servant.
  Nature, 431, 142.  
14991001 L.Xu, and J.Massagué (2004).
Nucleocytoplasmic shuttling of signal transducers.
  Nat Rev Mol Cell Biol, 5, 209-219.  
14720321 M.Kondo, H.Suzuki, K.Takehara, K.Miyazono, and M.Kato (2004).
Transforming growth factor-beta signaling is differentially inhibited by Smad2D450E and Smad3D407E.
  Cancer Sci, 95, 12-17.  
14746809 M.de Caestecker (2004).
The transforming growth factor-beta superfamily of receptors.
  Cytokine Growth Factor Rev, 15, 1.  
14729957 R.A.Randall, M.Howell, C.S.Page, A.Daly, P.A.Bates, and C.S.Hill (2004).
Recognition of phosphorylated-Smad2-containing complexes by a novel Smad interaction motif.
  Mol Cell Biol, 24, 1106-1121.  
15452148 R.S.Peterson, R.A.Andhare, K.T.Rousche, W.Knudson, W.Wang, J.B.Grossfield, R.O.Thomas, R.E.Hollingsworth, and C.B.Knudson (2004).
CD44 modulates Smad1 activation in the BMP-7 signaling pathway.
  J Cell Biol, 166, 1081-1091.  
14555996 B.Y.Qin, C.Liu, S.S.Lam, H.Srinath, R.Delston, J.J.Correia, R.Derynck, and K.Lin (2003).
Crystal structure of IRF-3 reveals mechanism of autoinhibition and virus-induced phosphoactivation.
  Nat Struct Biol, 10, 913-921.
PDB code: 1qwt
12742164 T.Reguly, and J.L.Wrana (2003).
In or out? The dynamics of Smad nucleocytoplasmic shuttling.
  Trends Cell Biol, 13, 216-220.  
12809600 Y.Shi, and J.Massagué (2003).
Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
  Cell, 113, 685-700.  
12440701 A.Mehra, and J.L.Wrana (2002).
TGF-beta and the Smad signal transduction pathway.
  Biochem Cell Biol, 80, 605-622.  
12154125 B.Y.Qin, S.S.Lam, J.J.Correia, and K.Lin (2002).
Smad3 allostery links TGF-beta receptor kinase activation to transcriptional control.
  Genes Dev, 16, 1950-1963.
PDB codes: 1mjs 1mk2
11818142 D.U.Kloos, C.Choi, and E.Wingender (2002).
The TGF-beta--Smad network: introducing bioinformatic tools.
  Trends Genet, 18, 96.  
11918675 F.Itoh, N.Divecha, L.Brocks, L.Oomen, H.Janssen, J.Calafat, S.Itoh, and P.Dijke Pt (2002).
The FYVE domain in Smad anchor for receptor activation (SARA) is sufficient for localization of SARA in early endosomes and regulates TGF-beta/Smad signalling.
  Genes Cells, 7, 321-331.  
11796104 J.L.Wrana (2002).
Phosphoserine-dependent regulation of protein-protein interactions in the Smad pathway.
  Structure, 10, 5-7.  
12191473 L.Xu, Y.Kang, S.Cöl, and J.Massagué (2002).
Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGFbeta signaling complexes in the cytoplasm and nucleus.
  Mol Cell, 10, 271-282.  
11850407 M.Davis, A.Hatzubai, J.S.Andersen, E.Ben-Shushan, G.Z.Fisher, A.Yaron, A.Bauskin, F.Mercurio, M.Mann, and Y.Ben-Neriah (2002).
Pseudosubstrate regulation of the SCF(beta-TrCP) ubiquitin ligase by hnRNP-U.
  Genes Dev, 16, 439-451.  
11920677 P.Ten Dijke, M.J.Goumans, F.Itoh, and S.Itoh (2002).
Regulation of cell proliferation by Smad proteins.
  J Cell Physiol, 191, 1.  
11782434 R.A.Randall, S.Germain, G.J.Inman, P.A.Bates, and C.S.Hill (2002).
Different Smad2 partners bind a common hydrophobic pocket in Smad2 via a defined proline-rich motif.
  EMBO J, 21, 145-156.  
12185845 S.Souchelnytskyi, A.Moustakas, and C.H.Heldin (2002).
TGF-beta signaling from a three-dimensional perspective: insight into selection of partners.
  Trends Cell Biol, 12, 304-307.  
11874485 T.L.McGaha, R.G.Phelps, H.Spiera, and C.Bona (2002).
Halofuginone, an inhibitor of type-I collagen synthesis and skin sclerosis, blocks transforming-growth-factor-beta-mediated Smad3 activation in fibroblasts.
  J Invest Dermatol, 118, 461-470.  
11779505 B.Y.Qin, B.M.Chacko, S.S.Lam, M.P.de Caestecker, J.J.Correia, and K.Lin (2001).
Structural basis of Smad1 activation by receptor kinase phosphorylation.
  Mol Cell, 8, 1303-1312.
PDB code: 1khu
11313456 C.Prunier, N.Ferrand, B.Frottier, M.Pessah, and A.Atfi (2001).
Mechanism for mutational inactivation of the tumor suppressor Smad2.
  Mol Cell Biol, 21, 3302-3313.  
11170295 J.Rich, A.Borton, and X.Wang (2001).
Transforming growth factor-beta signaling in cancer.
  Microsc Res Tech, 52, 363-373.  
11779503 J.W.Wu, M.Hu, J.Chai, J.Seoane, M.Huse, C.Li, D.J.Rigotti, S.Kyin, T.W.Muir, R.Fairman, J.Massagué, and Y.Shi (2001).
Crystal structure of a phosphorylated Smad2. Recognition of phosphoserine by the MH2 domain and insights on Smad function in TGF-beta signaling.
  Mol Cell, 8, 1277-1289.
PDB code: 1khx
11707292 J.Yue, and K.M.Mulder (2001).
Transforming growth factor-beta signal transduction in epithelial cells.
  Pharmacol Ther, 91, 1.  
  11532220 L.Attisano, and S.Tuen Lee-Hoeflich (2001).
The Smads.
  Genome Biol, 2, REVIEWS3010.  
11438668 M.Furuhashi, K.Yagi, H.Yamamoto, Y.Furukawa, S.Shimada, Y.Nakamura, A.Kikuchi, K.Miyazono, and M.Kato (2001).
Axin facilitates Smad3 activation in the transforming growth factor beta signaling pathway.
  Mol Cell Biol, 21, 5132-5141.  
11583628 M.Huse, T.W.Muir, L.Xu, Y.G.Chen, J.Kuriyan, and J.Massagué (2001).
The TGF beta receptor activation process: an inhibitor- to substrate-binding switch.
  Mol Cell, 8, 671-682.
PDB code: 1ias
11223879 Y.Shi (2001).
Structural insights on Smad function in TGFbeta signaling.
  Bioessays, 23, 223-232.  
11106755 D.Durocher, I.A.Taylor, D.Sarbassova, L.F.Haire, S.L.Westcott, S.P.Jackson, S.J.Smerdon, and M.B.Yaffe (2000).
The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms.
  Mol Cell, 6, 1169-1182.
PDB code: 1g6g
10660041 J.L.Wrana (2000).
Regulation of Smad activity.
  Cell, 100, 189-192.  
10708948 J.L.Wrana, and L.Attisano (2000).
The Smad pathway.
  Cytokine Growth Factor Rev, 11, 5.  
10775259 J.Massagué, and D.Wotton (2000).
Transcriptional control by the TGF-beta/Smad signaling system.
  EMBO J, 19, 1745-1754.  
10712925 L.Attisano, and J.L.Wrana (2000).
Smads as transcriptional co-modulators.
  Curr Opin Cell Biol, 12, 235-243.  
10996525 S.A.Pangas, and T.K.Woodruff (2000).
Activin signal transduction pathways.
  Trends Endocrinol Metab, 11, 309-314.  
11106403 S.Itoh, F.Itoh, M.J.Goumans, and P.Ten Dijke (2000).
Signaling of transforming growth factor-beta family members through Smad proteins.
  Eur J Biochem, 267, 6954-6967.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.

 

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