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The Open Protein Structure Annotation Network
PDB Keyword
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1s4y

    Table of contents
    1. 1. Protein Summary
    2. 2. Ligand Summary
    3. 3. References

    Title A Flexible Activin Explains the Membrane-Dependent Cooperative Assembly of TGF-beta Family Receptors. Mol.Cell 15 485-489 2004
    Site JCSG
    PDB Id 1s4y Target Id 356547
    Molecular Characteristics
    Source Mus musculus
    Alias Ids TPS1363,114727 Molecular Weight 11360.92 Da.
    Residues 96 Isoelectric Point 4.67
    Sequence etreciyynanwelertnqsglercegeqdkrlhcyaswrnssgtielvkkgcwlddfncydrqecvat eenpqvyfcccegnfcnerfthlpepg
      BLAST   FFAS

    Structure Determination
    Method XRAY Chains 1
    Resolution (Å) 2.30 Rfree 0.28615
    Matthews' coefficent 2.60 Rfactor 0.20611
    Waters 177 Solvent Content 53.78

    Ligand Information
    Ligands
    Metals

    Jmol

     
    Google Scholar output for 1s4y
    1. A flexible activin explains the membrane-dependent cooperative assembly of TGF-_ family receptors
    J Greenwald, ME Vega, GP Allendorph, WH Fischer - Molecular cell, 2004 - Elsevier
     
    2. Structural basis for the inhibition of activin signalling by follistatin
    AE Harrington, SA Morris-Triggs, BT Ruotolo - The EMBO , 2006 - nature.com
     
    3. A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor
    D Weber, A Kotzsch, J Nickel, S Harth - BMC structural , 2007 - w02.biomedcentral.com
     
    4. Conserved structural determinants in three_fingered protein domains
    A Galat, G Gross, P Drevet, A Sato, A Mnez - FEBS Journal, 2008 - Wiley Online Library
     
    5. Common structural traits for cystine knot domain of the TGF_ superfamily of proteins and three-fingered ectodomain of their cellular receptors
    A Galat - Cellular and Molecular Life Sciences, 2011 - Springer
     
    6. Homology modeling and molecular evolution analysis of myostatin
    Y XIE, X XUE, H YIN, R TANG, J SU, K SONG - Zoological , 2008 - bioline.org.br
     
    7. A Host-Guest Relationship in Bone Morphogenetic Protein Receptor-II Defines Specificity in Ligand-Receptor Recognition
    LCC Yeh, WF Falcon, A Garces, JC Lee, JC Lee - Biochemistry, 2012 - ACS Publications
     
    8. Computational design, construction, and characterization of a set of specificity determining residues in proteinprotein interactions
    C Nagao, N Izako, S Soga, SH Khan - Proteins: Structure, , 2012 - Wiley Online Library
     
    9. 3D Protein Structure Prediction using probabilistic methods
    HH Guo - 2010 - sst.unisim.edu.sg
     
    10. Protein_protein docking by shape_complementarity and property matching
    T Geppert, E Proschak - Journal of Computational , 2010 - Wiley Online Library
     

    Protein Summary

    Activins are members of the TGF-beta superfamily. Originally discovered for their ability to induce RSH expression, activins were subsequently shown to regulate cell differentiation and proliferation, reproduction, wound healing and the inflammatory response in a variety of tissues (1). Disregulation of TGF-beta signaling has been implicated in a number of cancers, as well as degenerative and vascular diseases (1). Consequently, the mechanisms of ligand-receptor interactions in this superfamily have been the focus of intense study.

    The activin dimer (A, B or AB) is generated via intra-subunit disulfide bond formation involving six conserved cysteine residues folding into a unique cystine knot structure (Fig. 1). Following disulfide formation, proteolytic cleavage removes almost 300 residues from the homo-dimeric precursor to generate the mature activin. Binding of dimeric activin to type II receptor results in activation of the type I receptor and subsequent phosphorylation of Smad proteins, leading to downstream propagation of signaling.





    Figure 1. Cystine knot motif in human activin A (pdb id: 1s4y). Six overlapping cysteines (Cys11-Cys81, Cys40-Cys113, Cys44-Cys115) stabilize the adjacent beta sheets. An additional disulfide (Cys4-Cys12), not part of the knot, is formed at the N-terminus.

    Previous structures of activin bound to activin receptor IIb extra-cellular domains (ActRIIb ECDs) have revealed drastic differences between the two ligand subunits (2, 3). The structure of the almost complete ECD of ActRIIb from mouse in complex with human activin A (4), reveals a third orientation of the ligand with respect to the receptor (Fig. 2), supporting the hypothesis that the activin dimer can adopt multiple orientations, some of which disrupt binding to the type I receptor interface while still retaining binding to intact type II receptor interfaces. The different orientations of the activin dimer, extended ("wings spread") or compact ("wings closed"), could thus account for the observed differences in affinity of activin for type I and type II receptors.





    Figure 2. The activin dimer can adopt a range of orientations. Left, activin (in blue) bound to two ActRIIb ECDs (in magenta) shows the activin dimer (pdb id: 1nys) in a compact ("wings closed") orientation. The helix constituting part of the type I receptor binding interface is disordered in this complex. Right, activin (in green) bound to two ActRIIb ECDs (in yellow) (pdb id: 1s4y) shows the activin dimer in a more extended ("wings spread") orientation. Both the helix and much of the dimer interface forming the type I receptor binding interface remain intact.

    Increasing evidence suggests that ligand-mediated assembly of TGF-beta receptors is independent of direct receptor-receptor interactions (3, 4). Cooperativity could be achieved by diffusion and stoichiometry constraints within biological membranes, with distinct receptor spacings immobilizing activin in a type I-binding competent orientation (4).

    Ligand Summary

    activin A dimer

    References

    Reviews

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