Article

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: 3.38). 11/2008; 47(46):11930-9. DOI: 10.1021/bi801059j
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
72 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: The design of functional polymer multilayer thin films with nanometer scale control is of great interest for biomedical applications such as tissue engineering, targeted drug delivery, controlled release system, and regenerative medicine. Various functions and properties of polymer thin films can be easily programmed and realized by the layer-by-layer assembly strategy, which is a facile and versatile deposition method to prepare well-defined biomedical multilayer platforms due to its benign process to prepare films under mild conditions and the capability of incorporating bioactive materials at a desired location within the films. Particularly, the fine tuning of physicochemical and biological properties of multilayer thin films is significantly important for designing novel biomedical platforms capable of adjusting the cellular functions. In this review, we focus on the overall background of the layer-by-layer assembly as well as the tuning of multilayer film properties and the programming of biological functions into the polymer thin films with a view on the control of cellular functions. Furthermore, we highlighted the recent achievements toward the design of novel biomedical platforms based on functionalized polymer multilayer thin films. Key wordsLayer-by-layer Assembly–Multilayer Thin Film(s)–Bio-functionalization–Cellular Function(s)–Biomedical Platform(s)
    Korean Journal of Chemical Engineering 01/2011; 28(5):1149-1160. · 1.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone morphogenetic proteins (BMPs) are secreted signaling proteins - they transduce their signals by assembling complexes comprised of one of three known type II receptors and one of four known type I receptors. BMP-9 binds and signals through the type I receptor Alk1, but not other Alks, while BMP-2, -4, and -7 bind and signal through Alk3, and the close homologue Alk6, but not Alk1. The present results, which include the determination of the Alk1 structure using NMR and identification of residues important for binding using SPR, show that the β-strand framework of Alk1 is highly similar to Alk3, yet there are significant differences in loops shown previously to be important for binding. The most pronounced difference is in the N-terminal portion of the β4-β5 loop, which is structurally ordered and includes a similarly placed but shorter helix in Alk1 compared to Alk3. The altered conformation of the β4-β5 loop, and to lesser extent β1-β2 loop, cause clashes when Alk1 is positioned onto BMP-9 in the manner that Alk3 is positioned onto BMP-2. This necessitates an alternative manner of binding, which is supported by a model of the BMP-9/Alk1 complex constructed using the program RosettaDock. The model shows that Alk1 is positioned similar to Alk3 but is rotated by 40 deg. The alternate positioning allows Alk1 to bind BMP-9 through a large hydrophobic interface, consistent with mutational analysis that identified several residues in the central portion of the β4-β5 loop that contribute significantly to binding and are nonconservatively substituted relative to the corresponding residues in Alk3.
    Biochemistry 07/2012; 51(32):6328-41. · 3.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bone Morphogenetic Proteins (BMPs), together with Transforming Growth Factor (TGF)-β and Activins/Inhibins constitute the TGF-β superfamily of ligands. This superfamily is formed by more than 30 structurally related secreted proteins. Since TGF-β members act as morphogens, either a strict relation between a particular ligand to a distinct cellular receptor and/or temporospatial expression patterns of ligands and receptors is expected. Instead, only a limited number of receptors exist implicating promiscuous interactions of ligands and receptors. Furthermore, in complex tissues a multitude of different ligands can be found, which signal via overlapping subsets of receptors. This raises the intriguing question how concerted interactions of different ligands and receptors generate highly specific cellular signals, which are required during development and tissue homeostasis.
    FEBS letters 03/2012; 586(14):1846-59. · 3.54 Impact Factor