The Solution Structure of BMPR-IA Reveals a Local Disorder-to-Order Transition upon BMP-2 Binding

Center of Integrated Protein Science (CIPSM) at the Technische Universitat Munchen, Lichtenbergstrasse 4, D-85747 Garching, Germany.
Biochemistry (Impact Factor: 3.02). 11/2008; 47(46):11930-9. DOI: 10.1021/bi801059j
Source: PubMed


The structure of the extracellular domain of BMP receptor IA was determined in solution by NMR spectroscopy and compared to its structure when bound to its ligand BMP-2. While most parts of the secondary structure are highly conserved between the bound and unbound forms, large conformational rearrangements can be observed in the beta4beta5 loop of BMPR-IA, which is in contact with BMP-2 and harbors the main binding determinants for the BMPR-IA-BMP-2 interaction. In its unbound form, helix alpha1 in BMPR-IA, which is in the center of the binding epitope for BMP-2, is missing. Since BMP-2 also shows conformational changes in the type I receptor epitope upon binding to BMPR-IA, both binding partners pass through an induced fit mechanism to adapt their binding interfaces to a given interaction surface. The inherent flexibility of both partners possibly explains the promiscuous ligand-receptor interaction observed in the BMP protein superfamily.

6 Reads
  • Source
    • "In the unbound state this pre-helix loop segment is also rather flexible allowing for geometrical adaptability to different receptor surface geometries. This observation together with the disordered and flexible ligand-binding epitope seen in the BMP type I receptors provides a mechanism for the pronounced ligand-receptor promiscuity seen in the BMP/GDF-subgroup of the TGF-β superfamily (Keller et al., 2004, Allendorph et al., 2007, Klages et al., 2008, Kotzsch et al., 2008, Saremba et al., 2008). Despite structural analyses showed that the pre-helix is flexible before receptor binding, the mutation L441P suggests that in the bound state a geometrically defined conformation is required for (high affinity) binding of BMP type I receptors (Kotzsch et al., 2009). "

    Full-text · Chapter · Oct 2012
  • Source
    • "Three crystal structures of the extracellular (EC) domain of BMPR-IA in complex with BMP-2 are described, showing that binding and structure of BMPR-IA are highly conserved, although crystallisation conditions varied in all three cases [9], [11], [14]. Recently, the NMR structure of unbound, free BMPR-IAEC was determined, showing that its core structure is largely superimposable upon the structure of the receptor bound to BMP-2 [15]. However, the binding epitope of BMPR-IA to BMP-2 differs markedly due to the absence of a short α-helix in the β4β5-loop of the free receptor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Members of the TGF-β superfamily are characterized by a highly promiscuous ligand-receptor interaction as is readily apparent from the numeral discrepancy of only seven type I and five type II receptors available for more than 40 ligands. Structural and functional studies have been used to address the question of how specific signals can be deduced from a limited number of receptor combinations and to unravel the molecular mechanisms underlying the protein-protein recognition that allow such limited specificity. In this study we have investigated how an antigen binding antibody fragment (Fab) raised against the extracellular domain of the BMP receptor type IA (BMPR-IA) recognizes the receptor's BMP-2 binding epitope and thereby neutralizes BMP-2 receptor activation. The crystal structure of the complex of the BMPR-IA ectodomain bound to the Fab AbD1556 revealed that the contact surface of BMPR-IA overlaps extensively with the contact surface for BMP-2 interaction. Although the structural epitopes of BMPR-IA to both binding partners coincides, the structures of BMPR-IA in the two complexes differ significantly. In contrast to the structural differences, alanine-scanning mutagenesis of BMPR-IA showed that the functional determinants for binding to the antibody and BMP-2 are almost identical. Comparing the structures of BMPR-IA bound to BMP-2 or bound to the Fab AbD1556 with the structure of unbound BMPR-IA shows that binding of BMPR-IA to its interaction partners follows a selection fit mechanism, possibly indicating that the ligand promiscuity of BMPR-IA is inherently encoded by structural adaptability. The functional and structural analysis of the BMPR-IA binding antibody AbD1556 mimicking the BMP-2 binding epitope may thus pave the way for the design of low-molecular weight synthetic receptor binders/inhibitors.
    Full-text · Article · Sep 2010 · PLoS ONE
  • Source
    • "On the basis of its homology to BMPR-IA, we also think that BMPR-IB passes through an induced fit mechanism upon ligand binding. NMR studies on the extracellular domain of free BMPR-IA showed that the b1b2-and especially the b4b5- loops are highly flexible and disordered in solution (Klages et al, 2008). Helix a1 is absent in free BMPR-IA (PDB entry 2K3G). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dysregulation of growth and differentiation factor 5 (GDF-5) signalling, a member of the TGF-beta superfamily, is strongly linked to skeletal malformation. GDF-5-mediated signal transduction involves both BMP type I receptors, BMPR-IA and BMPR-IB. However, mutations in either GDF-5 or BMPR-IB lead to similar phenotypes, indicating that in chondrogenesis GDF-5 signalling seems to be exclusively mediated through BMPR-IB. Here, we present structural insights into the GDF-5:BMPR-IB complex revealing how binding specificity for BMPR-IB is generated on a molecular level. In BMPR-IB, a loop within the ligand-binding epitope functions similar to a latch allowing high-affinity binding of GDF-5. In BMPR-IA, this latch is in a closed conformation leading to steric repulsion. The new structural data now provide also a molecular basis of how phenotypically relevant missense mutations in GDF-5 might impair receptor binding and activation.
    Full-text · Article · Mar 2009 · The EMBO Journal
Show more