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Influence of WFIKKN 1 on BMP 1‐mediated activation of latent myostatin
Author(s) -
Szláma György,
Vásárhelyi Viktor,
Trexler Mária,
Patthy László
Publication year - 2016
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/febs.13938
Subject(s) - cleavage (geology) , furin , enhancer , myostatin , biology , chemistry , biochemistry , transcription factor , enzyme , gene , paleontology , fracture (geology)
The NTR domain of WFIKKN 1 protein has been shown to have significant affinity for the prodomain regions of promyostatin and latent myostatin but the biological significance of these interactions remained unclear. In view of its role as a myostatin antagonist, we tested the assumption that WFIKKN 1 inhibits the release of myostatin from promyostatin and/or latent myostatin. WFIKKN 1 was found to have no effect on processing of promyostatin by furin, the rate of cleavage of latent myostatin by BMP 1, however, was significantly enhanced in the presence of WFIKKN 1 and this enhancer activity was superstimulated by heparin. Unexpectedly, WFIKKN 1 was also cleaved by BMP 1 and our studies have shown that the KKN 1 fragment generated by BMP 1‐cleavage of WFIKKN 1 contributes most significantly to the observed enhancer activity. Analysis of a pro‐ TGF ‐β ‐based homology model of homodimeric latent myostatin revealed that the BMP 1‐cleavage sites are buried and not readily accessible to BMP 1. In view of this observation, the most plausible explanation for the BMP 1‐enhancer activity of the KKN 1 fragment is that it shifts a conformational equilibrium of latent myostatin from the closed circular structure of the homodimer to a more open form, making the cleavage sites more accessible to BMP 1. On the other hand, the observation that the enhancer activity of KKN 1 is superstimulated in the presence of heparin is explained by the fact KKN 1, latent myostatin, and BMP 1 have affinity for heparin and these interactions with heparin increase the local concentrations of the reactants thereby facilitating the action of BMP 1. Enzymes Furin: EC 3.4.21.75 ; BMP1, bone morphogentic protein 1 or procollagen C‐endopeptidase: EC 3.4.24.19 .