Abstract
BackgroundTransforming growth factor (TGF)β 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.ResultsIn 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.ConclusionBinding 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.
Highlights
Transforming growth factor (TGF)β superfamily members transduce signals by oligomerizing two classes of serine/threonine kinase receptors, termed type I and type II
Ectodomains (ECDs) of the bacterially derived receptors bone morphogenic proteins (BMPs) receptor (BMPR)-IA, BMPR-IB and activin receptor (ActR)-IIB were purified to homogeneity by affinity chromatography employing a bone morphogenetic protein 2 (BMP2) affinity resin
Purification of only monomeric receptor proteins could be achieved since only monomeric ECDs bound to and were recovered from BMP2 affinity columns
Summary
Transforming growth factor (TGF)β superfamily members transduce signals by oligomerizing two classes of serine/threonine kinase receptors, termed type I and type II. In the adult organism these factors exhibit a broad range of biological effects and control various processes during regeneration and tissue repair such as growth, growth inhibition, differentiation, apoptosis, and secretion [6,7]. Based on their functional and sequence similarities TGFβ members can be divided into several subfamilies: the TGFβs (TGFβ1, β2, and β3), activins (activin A, B, C, E), BMP2s (BMP2, 4), BMP7s (BMP5, 6, 7), GDF5s (GDF5, 6, 7) and others [1,8]. Since members of the TGFβ superfamily transduce signals via a heterooligomeric receptor system, differences in binding affinities and specificities might generate a multiplicity of ligand-receptor complexes with different signaling properties, allowing cellular responses that differ in quality and quantity
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