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Type I receptor binding of bone morphogenetic protein 6 is dependent on N‐glycosylation of the ligand
Author(s) -
Saremba Stefan,
Nickel Joachim,
Seher Axel,
Kotzsch Alexander,
Sebald Walter,
Mueller Thomas D.
Publication year - 2008
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2007.06187.x
Subject(s) - bone morphogenetic protein , receptor , glycosylation , chemistry , microbiology and biotechnology , epitope , bone morphogenetic protein 10 , acvr2b , activin receptor , protein subunit , biochemistry , biology , tgf beta signaling pathway , bone morphogenetic protein 7 , genetics , antibody , gene
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. 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‐β 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.