BMP-binding modules in chordin: a model for signalling regulation in the extracellular space

A number of genetic and molecular studies have implicated Chordin in the re gulation of dorsoventral patterning during gastrulation, Chordin, a BMP ant agonist of 120 kDa, contains four small (about 70 amino acids each) cystein e-rich domains (CRs) of unknown function. In this study, we show that the C hordin CRs define a novel protein module for the binding and regulation of BMPs. The biological activity of Chordin resides in the CRs, especially in CR1 and CR3, which have dorsalizing activity in Xenopus embryo assays and b ind BMP4 with dissociation constants in the nanomolar range, The activity o f individual CRs, however, is 5- to 10-fold lower than that of full-length Chordin, These results shed light on the molecular mechanism by which Chord in/BMP complexes are regulated by the metalloprotease Xolloid, which cleave s in the vicinity of CR1 and CR3 and would release CR/BMP complexes with lo wer anti-BMP activity than intact Chordin, CR domains are found in other ex tracellular proteins such as procollagens. Full-length Xenopus procollagen IIA mRNA has dorsalizing activity in embryo microinjection assays and the C R domain is required for this activity. Similarly, a C, elegans cDNA contai ning five CR domains induces secondary axes in injected Xenopus embryos. Th ese results suggest that CR modules may function in a number of extracellul ar proteins to regulate growth factor signalling.