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PLoS Biol 2023 Aug 01;218:e3002272. doi: 10.1371/journal.pbio.3002272.
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SMOC-1 interacts with both BMP and glypican to regulate BMP signaling in C. elegans.

DeGroot MS , Williams B , Chang TY , Maas Gamboa ML , Larus IM , Hong G , Fromme JC , Liu J .

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-binding (EC) 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.

PubMed ID: 37590248
PMC ID: PMC10464977
Article link: PLoS Biol
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: bmp2 bmp4 ccs fst furin gpc1 gpc3 gpi mcf2 myc smoc1
GO keywords: BMP signaling pathway

Article Images: [+] show captions
References [+] :
Abouzeid, Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome. 2011, Pubmed