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

Hojoon Lee, Fabio A. Mendes, Jean Louis Plouhinec, Edward M. De Robertis

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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-β (TGF-β) 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.

Original languageEnglish (US)
Pages (from-to)2551-2562
Number of pages12
JournalGenes and Development
Volume23
Issue number21
DOIs
StatePublished - Nov 1 2009

Keywords

  • BMP
  • BMP1
  • CUB domain
  • Chordin
  • Tolloid

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Fingerprint Dive into the research topics of 'Enzymatic regulation of pattern: BMP4 binds CUB domains of Tolloids and inhibits proteinase activity'. Together they form a unique fingerprint.

Cite this