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XB-ART-40580
Genes Dev. November 1, 2009; 23 (21): 2551-62.

Enzymatic regulation of pattern: BMP4 binds CUB domains of Tolloids and inhibits proteinase activity.

Lee HX , Mendes FA , Plouhinec JL , De Robertis EM .


Abstract
In Xenopus embryos, a dorsal-ventral patterning gradient is generated by diffusing Chordin/bone morphogenetic protein (BMP) complexes cleaved by BMP1/Tolloid metalloproteinases in the ventral side. We developed a new BMP1/Tolloid assay using a fluorogenic Chordin peptide substrate and identified an unexpected negative feedback loop for BMP4, in which BMP4 inhibits Tolloid enzyme activity noncompetitively. BMP4 binds directly to the CUB (Complement 1r/s, Uegf [a sea urchin embryonic protein] and BMP1) domains of BMP1 and Drosophila Tolloid with high affinity. Binding to CUB domains inhibits BMP4 signaling. These findings provide a molecular explanation for a long-standing genetical puzzle in which antimorphic Drosophila tolloid mutant alleles displayed anti-BMP effects. The extensive Drosophila genetics available supports the relevance of the interaction described here at endogenous physiological levels. Many extracellular proteins contain CUB domains; the binding of CUB domains to BMP4 suggests a possible general function in binding transforming growth factor-beta (TGF-beta) superfamily members. Mathematical modeling indicates that feedback inhibition by BMP ligands acts on the ventral side, while on the dorsal side the main regulator of BMP1/Tolloid enzymatic activity is the binding to its substrate, Chordin.

PubMed ID: 19884260
PMC ID: PMC2779747
Article link: Genes Dev.
Grant support: HD21502-23 NICHD NIH HHSHoward Hughes Medical Institute , R01 HD021502-23 NICHD NIH HHS , R01 HD021502 NICHD NIH HHS

Genes referenced: bmp1 bmp4 bmp7.1 bmper chrd dspp fst gtf2ird1 nog otx2 pclo sox2 tgfb1 tll1 tll2
Antibodies referenced:
Morpholinos referenced: chrd MO1
Article Images: [+] show captions

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