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protein ligands metals Protein-protein interface(s) links
Signaling protein PDB id
2b0u
Jmol
Contents
Protein chains
116 a.a. *
287 a.a. *
Ligands
MLI ×4
MPD
Metals
IR3 ×5
Waters ×141
* Residue conservation analysis
PDB id:
2b0u
Name: Signaling protein
Title: The structure of the follistatin:activin complex
Structure: Inhibin beta a chain. Chain: a, b. Fragment: activin (mature form). Synonym: activin beta-a chain, erythroid differentiation pr edf. Engineered: yes. Follistatin. Chain: c, d. Fragment: follistatin-288.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: inhba. Expressed in: cricetulus griseus. Expression_system_taxid: 10029. Expression_system_cell: ovary. Gene: fst.
Biol. unit: Tetramer (from PQS)
Resolution:
2.80Å     R-factor:   0.265     R-free:   0.297
Authors: T.B.Thompson,T.F.Lerch,R.W.Cook,T.K.Woodruff,T.S.Jardetzky
Key ref:
T.B.Thompson et al. (2005). The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding. Dev Cell, 9, 535-543. PubMed id: 16198295 DOI: 10.1016/j.devcel.2005.09.008
Date:
14-Sep-05     Release date:   11-Oct-05    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P08476  (INHBA_HUMAN) -  Inhibin beta A chain
Seq:
Struc: 		426 a.a.
116 a.a.
Protein chains
Pfam   ArchSchema ?
P19883  (FST_HUMAN) -  Follistatin
Seq:
Struc: 		344 a.a.
287 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   3 terms 
  Biological process     gamete generation   14 terms 
  Biochemical function     signal transducer activity     5 terms  

 

 
DOI no: 10.1016/j.devcel.2005.09.008 Dev Cell 9:535-543 (2005)
PubMed id: 16198295  
 
 
The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding.
T.B.Thompson, T.F.Lerch, R.W.Cook, T.K.Woodruff, T.S.Jardetzky.
 
  ABSTRACT  
 
TGF-beta ligands stimulate diverse cellular differentiation and growth responses by signaling through type I and II receptors. Ligand antagonists, such as follistatin, block signaling and are essential regulators of physiological responses. Here we report the structure of activin A, a TGF-beta ligand, bound to the high-affinity antagonist follistatin. Two follistatin molecules encircle activin, neutralizing the ligand by burying one-third of its residues and its receptor binding sites. Previous studies have suggested that type I receptor binding would not be blocked by follistatin, but the crystal structure reveals that the follistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif and occupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can be explained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The mode of ligand binding by follistatin has important implications for its ability to neutralize homo- and heterodimeric ligands of this growth factor family.
 
  Selected figure(s)  
 
Figure 1.
Figure 1. Overview of the Follistatin:Activin A Complex 		Figure 6.
Figure 6. Differing Modes of Ligand Complex Formation and Antagonism
 
  The above figures are reprinted by permission from Cell Press: Dev Cell (2005, 9, 535-543) copyright 2005.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20938711 R.Silva-García, and G.Rico-Rosillo (2011).
Anti-inflammatory defense mechanisms of Entamoeba histolytica.
  Inflamm Res, 60, 111-117.  
20209104 J.Zhu, E.L.Braun, S.Kohno, M.Antenos, E.Y.Xu, R.W.Cook, S.J.Lin, B.C.Moore, L.J.Guillette, T.S.Jardetzky, and T.K.Woodruff (2010).
Phylogenomic analyses reveal the evolutionary origin of the inhibin alpha-subunit, a unique TGFbeta superfamily antagonist.
  PLoS One, 5, e9457.  
19106105 A.L.Blount, K.Schmidt, N.J.Justice, W.W.Vale, W.H.Fischer, and L.M.Bilezikjian (2009).
FoxL2 and Smad3 Coordinately Regulate Follistatin Gene Transcription.
  J Biol Chem, 284, 7631-7645.  
19641179 C.A.VandeVoort, N.R.Mtango, Y.S.Lee, G.W.Smith, and K.E.Latham (2009).
Differential effects of follistatin on nonhuman primate oocyte maturation and pre-implantation embryo development in vitro.
  Biol Reprod, 81, 1139-1146.  
19644449 J.N.Cash, C.A.Rejon, A.C.McPherron, D.J.Bernard, and T.B.Thompson (2009).
The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding.
  EMBO J, 28, 2662-2676.
PDB code: 3hh2
  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.  
19324848 M.A.Akinci, H.Turner, M.Taveras, A.Barash, Z.Wang, P.Reinach, and J.M.Wolosin (2009).
Molecular profiling of conjunctival epithelial side-population stem cells: atypical cell surface markers and sources of a slow-cycling phenotype.
  Invest Ophthalmol Vis Sci, 50, 4162-4172.  
19692420 M.J.Prodoehl, N.Hatzirodos, H.F.Irving-Rodgers, Z.Z.Zhao, J.N.Painter, T.E.Hickey, M.A.Gibson, W.E.Rainey, B.R.Carr, H.D.Mason, R.J.Norman, G.W.Montgomery, and R.J.Rodgers (2009).
Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries.
  Mol Hum Reprod, 15, 829-841.  
19419965 M.M.Phelan, C.T.Thai, D.C.Soares, R.T.Ogata, P.N.Barlow, and J.Bramham (2009).
Solution Structure of Factor I-like Modules from Complement C7 Reveals a Pair of Follistatin Domains in Compact Pseudosymmetric Arrangement.
  J Biol Chem, 284, 19637-19649.
PDB code: 2wcy
19141859 N.C.Robson, H.Wei, T.McAlpine, N.Kirkpatrick, J.Cebon, and E.Maraskovsky (2009).
Activin-A attenuates several human natural killer cell functions.
  Blood, 113, 3218-3225.  
19273500 Y.Xia, and A.L.Schneyer (2009).
The biology of activin: recent advances in structure, regulation and function.
  J Endocrinol, 202, 1.  
  18350601 A.Deli, E.Kreidl, S.Santifaller, B.Trotter, K.Seir, W.Berger, R.Schulte-Hermann, C.Rodgarkia-Dara, and M.Grusch (2008).
Activins and activin antagonists in hepatocellular carcinoma.
  World J Gastroenterol, 14, 1699-1709.  
18184649 A.L.Blount, J.M.Vaughan, W.W.Vale, and L.M.Bilezikjian (2008).
A Smad-binding element in intron 1 participates in activin-dependent regulation of the follistatin gene.
  J Biol Chem, 283, 7016-7026.  
18535106 A.L.Schneyer, Y.Sidis, A.Gulati, J.L.Sun, H.Keutmann, and P.A.Krasney (2008).
Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin.
  Endocrinology, 149, 4589-4595.  
18077144 D.Bickel, R.Shah, S.C.Gesualdi, and T.E.Haerry (2008).
Drosophila Follistatin exhibits unique structural modifications and interacts with several TGF-beta family members.
  Mech Dev, 125, 117-129.  
18074148 D.J.Macqueen, and I.A.Johnston (2008).
Evolution of follistatin in teleosts revealed through phylogenetic, genomic and expression analyses.
  Dev Genes Evol, 218, 1.  
18474281 M.E.Carlson, H.S.Silva, and I.M.Conboy (2008).
Aging of signal transduction pathways, and pathology.
  Exp Cell Res, 314, 1951-1961.  
18156495 N.C.Robson, D.J.Phillips, T.McAlpine, A.Shin, S.Svobodova, T.Toy, V.Pillay, N.Kirkpatrick, D.Zanker, K.Wilson, I.Helling, H.Wei, W.Chen, J.Cebon, and E.Maraskovsky (2008).
Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production.
  Blood, 111, 2733-2743.  
18768470 R.Stamler, H.T.Keutmann, Y.Sidis, C.Kattamuri, A.Schneyer, and T.B.Thompson (2008).
The Structure of FSTL3{middle dot}Activin A Complex: DIFFERENTIAL BINDING OF N-TERMINAL DOMAINS INFLUENCES FOLLISTATIN-TYPE ANTAGONIST SPECIFICITY.
  J Biol Chem, 283, 32831-32838.
PDB code: 3b4v
18397882 Y.Makanji, K.L.Walton, M.C.Wilce, K.L.Chan, D.M.Robertson, and C.A.Harrison (2008).
Suppression of inhibin A biological activity by alterations in the binding site for betaglycan.
  J Biol Chem, 283, 16743-16751.  
18000526 B.Schmierer, and C.S.Hill (2007).
TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.
  Nat Rev Mol Cell Biol, 8, 970-982.  
17483092 J.L.Zhang, Y.Huang, L.Y.Qiu, J.Nickel, and W.Sebald (2007).
von Willebrand factor type C domain-containing proteins regulate bone morphogenetic protein signaling through different recognition mechanisms.
  J Biol Chem, 282, 20002-20014.  
17140726 T.F.Lerch, M.Xu, T.S.Jardetzky, K.E.Mayo, I.Radhakrishnan, R.Kazer, L.D.Shea, and T.K.Woodruff (2007).
The structures that underlie normal reproductive function.
  Mol Cell Endocrinol, 267, 1-5.  
17409095 T.F.Lerch, S.Shimasaki, T.K.Woodruff, and T.S.Jardetzky (2007).
Structural and biophysical coupling of heparin and activin binding to follistatin isoform functions.
  J Biol Chem, 282, 15930-15939.
PDB code: 2p6a
16482093 E.M.De Robertis (2006).
Spemann's organizer and self-regulation in amphibian embryos.
  Nat Rev Mol Cell Biol, 7, 296-302.  
16384533 A.J.Gore, D.P.Philips, W.L.Miller, and D.J.Bernard (2005).
Differential regulation of follicle stimulating hormone by activin A and TGFB1 in murine gonadotropes.
  Reprod Biol Endocrinol, 3, 73.  
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.