Bone morphogenetic protein (BMP)-6, BMP-5, BMP-7 and BMP-8 constitute a subgroup of the transforming growth factor (TGF)-b superfamily proteins. Besides the ability of BMP-6 to induce bone formation at ectopic and orthotopic sites, BMP-6 transcripts have been localized in numerous studies to developing organs and tissues, such as the heart, the brain, and hypertrophic cartilage, throughout the developing skeletal system, and also to adult tissues, such as brain and uterus [1][2][3][4][5]. BMP-6 and its closest relative, BMP-7, show overlapping expression patterns as well as overlapping functions. For example, in the developing heart, BMP-6 and BMP-7 are required for cushion formation and septation [5]. In the brain, BMP-6 and Bone morphogenetic proteins (BMPs), together with transforming growth factor (TGF)-b and activins ⁄ inhibins, constitute the TGF-b superfamily of ligands. This superfamily is formed by more than 30 structurally related secreted proteins. The crystal structure of human BMP-6 was determined to a resolution of 2.1 Å ; the overall structure is similar to that of other TGF-b superfamily ligands, e.g. BMP-7. The asymmetric unit contains the full dimeric BMP-6, indicating possible asymmetry between the two monomeric subunits. Indeed, the conformation of several loops differs between both monomers. In particular, the prehelix loop, which plays a crucial role in the type I receptor interactions of BMP-2, adopts two rather different conformations in BMP-6, indicating possible dynamic flexibility of the prehelix loop in its unbound conformation. Flexibility of this loop segment has been discussed as an important feature required for promiscuous binding of different type I receptors to BMPs. Further studies investigating the interaction of BMP-6 with different ectodomains of type I receptors revealed that N-glycosylation at Asn73 of BMP-6 in the wrist epitope is crucial for recognition by the activin receptor type I. In the absence of the carbohydrate moiety, activin receptor type I-mediated signaling of BMP-6 is totally diminished. Thus, flexibility within the binding epitope of BMP-6 and an unusual recognition motif, i.e. an N-glycosylation motif, possibly play an important role in type I receptor specificity of BMP-6.

Interleukin-5 (IL-5) is the key mediator for the function of eosinophil granulocytes, whose deregulation is characteristic of hypereosinophilic diseases and presumably contributes to allergic asthma. IL-5 signaling involves two transmembrane receptors, IL-5Rα and the common β chain, which upon formation of the ternary complex activate the JAK/STAT signaling cascade. To investigate the mechanism underlying ligand-receptor recognition, we determined the structure of IL-5 bound to the extracellular domain of IL-5Rα. IL-5 makes contact with all three fibronectin III-like domains of IL-5Rα, with the receptor architecture resembling a wrench. Mutagenesis data provide evidence that this wrench-like architecture is likely preformed. The structure demonstrates that for steric reasons, homodimeric IL-5 can bind only one receptor molecule, even though two equivalent receptor-binding sites exist. In regard to strong efforts being made to develop IL-5 antagonists for treating asthma and hypereosinophilic diseases, the advances in molecular understanding provided by this structure are of greatest value.

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