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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred

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Volume 385, Issue 8 (Aug 2004)

Issues

Molecular recognition in bone morphogenetic protein (BMP)/receptor interaction

Walter Sebald
  • Physiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, D-97074 Würzburg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Joachim Nickel
  • Physiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, D-97074 Würzburg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jin-Li Zhang
  • Physiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, D-97074 Würzburg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Thomas D. Mueller
  • Physiologische Chemie II, Theodor-Boveri-Institut für Biowissenschaften (Biozentrum) der Universität Würzburg, D-97074 Würzburg, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2005-06-01 | DOI: https://doi.org/10.1515/BC.2004.086

Abstract

Bone morphogenetic proteins (BMPs) and other members of the TGF-β superfamily are secreted signalling proteins determining the development, maintenance and regeneration of tissues and organs. These dimeric proteins bind, via multiple epitopes, two types of signalling receptor chains and numerous extracellular modulator proteins that stringently control their activity. Crystal structures of free ligands and of complexes with type I and type II receptor extracellular domains and with the modulator protein Noggin reveal structural epitopes that determine the affinity and specificity of the interactions. Modelling of a ternary complex BMP/(BMPR-IAEC)2/(ActR-IIEC)2 suggests a mechanism of receptor activation that does not rely on direct contacts between extracellular domains of the receptors. Mutational and interaction analyses indicate that the large hydrophobic core of the interface of BMP-2 (wrist epitope) with the type I receptor does not provide a hydrophobic hot spot for binding. Instead, main chain amide and carbonyl groups that are completely buried in the contact region represent major binding determinants. The affinity between ligand and receptor chains is probably strongly increased by two-fold interactions of the dimeric ligand and receptor chains that exist as homodimers in the membrane (avidity effects). BMP muteins with disrupted epitopes for receptor chains or modulator proteins provide clues for drug design and development.

Keywords: binding determinants; functional epitope; modulator protein; muteins; receptor ectodomain; TGF-β-like protein

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Published Online: 2005-06-01

Published in Print: 2004-08-01


Citation Information: Biological Chemistry, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/BC.2004.086.

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