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- Title
SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans.
- Authors
DeGroot, Melisa S.; Williams, Byron; Chang, Timothy Y.; Maas Gamboa, Maria L.; Larus, Isabel M.; Hong, Garam; Fromme, J. Christopher; Liu, Jun
- Abstract
Secreted modular calcium-binding proteins (SMOCs) are conserved matricellular proteins found in organisms from Caenorhabditis elegans to humans. SMOC homologs characteristically contain 1 or 2 extracellular calcium (EC)-binding domain(s) and 1 or 2 thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate proteoglycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans. We showed that CeSMOC-1 binds to the heparin sulfate proteoglycan GPC3 homolog LON-2/glypican, as well as the mature domain of the BMP2/4 homolog DBL-1. Moreover, CeSMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between CeSMOC-1 and LON-2/glypican is mediated specifically by the EC domain of CeSMOC-1, while the full interaction between CeSMOC-1 and DBL-1/BMP requires full-length CeSMOC-1. We provide both in vitro biochemical and in vivo functional evidence demonstrating that CeSMOC-1 functions both negatively in a LON-2/glypican-dependent manner and positively in a DBL-1/BMP-dependent manner to regulate BMP signaling. We further showed that in silico, Drosophila and vertebrate SMOC proteins can also bind to mature BMP dimers. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling. Cell-cell signaling needs to be precisely controlled to ensure proper development and homeostasis. This study shows that the conserved secreted modular calcium binding protein, SMOC, regulates bone morphogenetic protein (BMP) signaling in the nematode C. elegans by binding to both BMP and glypican.
- Subjects
CAENORHABDITIS elegans; BONE morphogenetic proteins; HEPARAN sulfate proteoglycans; CARRIER proteins; CHONDROITIN sulfate proteoglycan
- Publication
PLoS Biology, 2023, Vol 21, Issue 8, p1
- ISSN
1544-9173
- Publication type
Article
- DOI
10.1371/journal.pbio.3002272