RRC ID 61979
Author Heinecke K, Seher A, Schmitz W, Mueller TD, Sebald W, Nickel J.
Title Receptor oligomerization and beyond: a case study in bone morphogenetic proteins.
Journal BMC Biol
Abstract BACKGROUND:Transforming growth factor (TGF)beta superfamily members transduce signals by oligomerizing two classes of serine/threonine kinase receptors, termed type I and type II. In contrast to the large number of ligands only seven type I and five type II receptors have been identified in mammals, implicating a prominent promiscuity in ligand-receptor interaction. Since a given ligand can usually interact with more than one receptor of either subtype, differences in binding affinities and specificities are likely important for the generation of distinct ligand-receptor complexes with different signaling properties.
RESULTS:In vitro interaction analyses showed two different prototypes of binding kinetics, 'slow on/slow off' and 'fast on/fast off'. Surprisingly, the binding specificity of ligands to the receptors of one subtype is only moderate. As suggested from the dimeric nature of the ligands, binding to immobilized receptors shows avidity due to cooperative binding caused by bivalent ligand-receptor interactions. To compare these in vitro observations to the situation in vivo, binding studies on whole cells employing homodimeric as well as heterodimeric bone morphogenetic protein 2 (BMP2) mutants were performed. Interestingly, low and high affinity binding sites were identified, as defined by the presence of either one or two BMP receptor (BMPR)-IA receptor chains, respectively. Both sites contribute to different cellular responses in that the high affinity sites allow a rapid transient response at low ligand concentrations whereas the low affinity sites facilitate sustained signaling but higher ligand concentrations are required.
CONCLUSION:Binding of a ligand to a single high affinity receptor chain functioning as anchoring molecule and providing sufficient complex stability allows the subsequent formation of signaling competent complexes. Another receptor of the same subtype, and up to two receptors of the other subtype, can then be recruited. Thus, the resulting receptor arrangement can principally consist of four different receptors, which is consistent with our interaction analysis showing low ligand-receptor specificity within one subtype class. For BMP2, further complexity is added by the fact that heterooligomeric signaling complexes containing only one type I receptor chain can also be found. This indicates that despite prominent ligand receptor promiscuity a manifold of diverse signals might be generated in this receptor limited system.
Volume 7
Pages 59
Published 2009-9-7
DOI 10.1186/1741-7007-7-59
PII 1741-7007-7-59
PMID 19735544
PMC PMC2749821
MeSH Activin Receptors / chemistry Activin Receptors / genetics Activin Receptors / isolation & purification Activin Receptors / metabolism Activins / chemistry Activins / genetics Activins / isolation & purification Activins / metabolism Animals Bacterial Proteins / chemistry Bacterial Proteins / genetics Bacterial Proteins / isolation & purification Bacterial Proteins / metabolism Binding Sites Biosensing Techniques Bone Morphogenetic Protein Receptors / chemistry* Bone Morphogenetic Protein Receptors / genetics Bone Morphogenetic Protein Receptors / isolation & purification Bone Morphogenetic Protein Receptors / metabolism* Bone Morphogenetic Proteins / chemistry Bone Morphogenetic Proteins / genetics Bone Morphogenetic Proteins / isolation & purification Bone Morphogenetic Proteins / metabolism* COS Cells Cell Line, Tumor Chlorocebus aethiops Cholic Acids / chemistry Detergents / chemistry Growth Differentiation Factor 5 / chemistry Growth Differentiation Factor 5 / genetics Growth Differentiation Factor 5 / isolation & purification Growth Differentiation Factor 5 / metabolism* Humans Immobilized Proteins / chemistry Immobilized Proteins / metabolism Kinetics Ligands Models, Biological Mutant Proteins / chemistry Mutant Proteins / metabolism Protein Binding Protein Interaction Domains and Motifs / physiology* Protein Isoforms Recombinant Fusion Proteins / chemistry Recombinant Fusion Proteins / metabolism Transfection
IF 6.765
Human and Animal Cells ATDC5(RCB0565)