PDBsum entry 1lr8

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Hormone/growth factor PDB id
Protein chain
73 a.a. *
Waters ×21
* Residue conservation analysis
PDB id:
Name: Hormone/growth factor
Title: Crystal structure of fs1, the heparin-binding domain of follistatin, complexed with the heparin analogue d-myo- inositol hexasulphate (ins6s)
Structure: Follistatin. Chain: a. Fragment: heparin-binding domain. Synonym: fs1. Engineered: yes
Source: Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
2.10Å     R-factor:   0.222     R-free:   0.251
Authors: C.A.Innis,M.Hyvonen
Key ref:
C.A.Innis and M.Hyvönen (2003). Crystal structures of the heparan sulfate-binding domain of follistatin. Insights into ligand binding. J Biol Chem, 278, 39969-39977. PubMed id: 12867435 DOI: 10.1074/jbc.M211284200
15-May-02     Release date:   29-Jul-03    
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Protein chain
Pfam   ArchSchema ?
P21674  (FST_RAT) -  Follistatin
344 a.a.
73 a.a.
Key:    PfamA domain  Secondary structure  CATH domain


DOI no: 10.1074/jbc.M211284200 J Biol Chem 278:39969-39977 (2003)
PubMed id: 12867435  
Crystal structures of the heparan sulfate-binding domain of follistatin. Insights into ligand binding.
C.A.Innis, M.Hyvönen.
Follistatin associates with transforming growth factor-beta-like growth factors such as activin or bone morphogenetic proteins to form an inactive complex, thereby regulating processes as diverse as embryonic development and cell secretion. Although an interaction between heparan sulfate chains present at the cell surface and follistatin has been recorded, the impact of this binding reaction on the follistatin-mediated inhibition of transforming growth factor-beta-like signaling remains unclear. To gain a structural insight into this interaction, we have solved the crystal structure of the presumed heparan sulfate-binding domain of follistatin, both alone and in complex with the small heparin analogs sucrose octasulfate and D-myo-inositol hexasulfate. In addition, we have confirmed the binding of the sucrose octasulfate and D-myo-inositol hexasulfate molecules to this follistatin domain and determined the association constants and stoichiometries of both interactions in solution using isothermal titration calorimetry. Overall, our results shed light upon the structure of this follistatin domain and reveal a novel conformation for a hinge region connecting epidermal growth factor-like and Kazal-like subdomains compared with the follistatin-like domain found in the extracellular matrix protein BM-40. Moreover, the crystallographic analysis of the two protein-ligand complexes mentioned above leads us to propose a potential location for the heparan sulfate-binding site on the surface of follistatin and to suggest the involvement of residues Asn80 and Arg86 in such a follistatin-heparin interaction.
  Selected figure(s)  
Figure 2.
FIG. 2. Fs1 structure. Left, ribbon diagram of the Fs1/SOS structure, highlighting secondary structure elements. Right, diagrams of the superimposed C[ ]traces for the Fs1 (red), Fs1/SOS (yellow), and Fs1/Ins6S (blue) structures; the loop involved in crystal contacts is circled, and the SOS and Ins6S are shown in stick representation. In both halves of this figure, disulfide bonds are depicted in white with red numbering, and secondary structure elements are labeled in dark blue. This figure and the following three-dimensional representations of molecules were generated using the program Molscript (50) and rendered with Raster3D (51).
Figure 5.
FIG. 5. Interactions between SOS/Ins6S and Fs1. A and B, binding of SOS (A) and Ins6S (B) to Fs1. Sulfate groups from these two heparin analogs are numbered, along with protein residues involved in the interaction. C, superimposition of the Fs1/SOS (ochre) and Fs1/Ins6S (blue) structures, showing the relative positioning of sulfate groups in the binding site. D-F, the interfaces between the heparin-binding region of one Fs1 molecule (blue) and the Kazal-like subdomain of one of its symmetry-related counterparts (ochre) are depicted for each of the three Fs1 structures. Residues involved in protein-protein and additional protein-ligand contacts are labeled, as are the sulfate groups interacting with the symmetry-related Fs1 molecules.
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2003, 278, 39969-39977) copyright 2003.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20545624 C.C.Rider, and B.Mulloy (2010).
Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists.
  Biochem J, 429, 1.  
19940118 E.Porten, B.Seliger, V.A.Schneider, S.Wöll, D.Stangel, R.Ramseger, and S.Kröger (2010).
The process-inducing activity of transmembrane agrin requires follistatin-like domains.
  J Biol Chem, 285, 3114-3125.  
20053992 S.Sarilla, S.Y.Habib, D.V.Kravtsov, A.Matafonov, D.Gailani, and I.M.Verhamme (2010).
Sucrose octasulfate selectively accelerates thrombin inactivation by heparin cofactor II.
  J Biol Chem, 285, 8278-8289.  
19845005 A.A.McFarlane, and J.Stetefeld (2009).
An interdomain disulfide bridge links the NtA and first FS domain in agrin.
  Protein Sci, 18, 2421-2428.
PDB code: 3i70
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
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
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.  
17089378 R.E.Saunders, C.Abarrategui-Garrido, V.Frémeaux-Bacchi, E.Goicoechea de Jorge, T.H.Goodship, M.López Trascasa, M.Noris, I.M.Ponce Castro, G.Remuzzi, S.Rodríguez de Córdoba, P.Sánchez-Corral, C.Skerka, P.F.Zipfel, and S.J.Perkins (2007).
The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models.
  Hum Mutat, 28, 222-234.  
16482217 A.E.Harrington, S.A.Morris-Triggs, B.T.Ruotolo, C.V.Robinson, S.Ohnuma, and M.Hyvönen (2006).
Structural basis for the inhibition of activin signalling by follistatin.
  EMBO J, 25, 1035-1045.
PDB codes: 2arp 2arv
16674666 Y.H.Chun, Y.Yamakoshi, J.W.Kim, T.Iwata, J.C.Hu, and J.P.Simmer (2006).
Porcine SPARC: isolation from dentin, cDNA sequence, and computer model.
  Eur J Oral Sci, 114, 78.  
16503157 Y.Yu, M.D.Sweeney, O.M.Saad, and J.A.Leary (2006).
Potential inhibitors of chemokine function: analysis of noncovalent complexes of CC chemokine and small polyanionic molecules by ESI FT-ICR mass spectrometry.
  J Am Soc Mass Spectrom, 17, 524-535.  
15384176 M.J.Cliff, A.Gutierrez, and J.E.Ladbury (2004).
A survey of the year 2003 literature on applications of isothermal titration calorimetry.
  J Mol Recognit, 17, 513-523.  
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.