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 regulation of dorsoventral patterning during gastrulation. Chordin, a BMP antagonist of 120 kDa, contains four small (about 70 amino acids each) cysteine-rich domains (CRs) of unknown function. In this study, we show that the Chordin 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 bind BMP4 with dissociation constants in the nanomolar range. The activity of 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 Chordin/BMP complexes are regulated by the metalloprotease Xolloid, which cleaves in the vicinity of CR1 and CR3 and would release CR/BMP complexes with lower anti-BMP activity than intact Chordin. CR domains are found in other extracellular proteins such as procollagens. Full-length Xenopus procollagen IIA mRNA has dorsalizing activity in embryo microinjection assays and the CR domain is required for this activity. Similarly, a C. elegans cDNA containing five CR domains induces secondary axes in injected Xenopus embryos. These results suggest that CR modules may function in a number of extracellular proteins to regulate growth factor signalling.
Larraín
J
J
Howard Hughes Medical Institute and Department of Biological Chemistry, University of California, Los Angeles, CA 90095-1662, USA.
Bachiller
D
D
Lu
B
B
Agius
E
E
Piccolo
S
S
De Robertis
E M
EM
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D001665:Binding Sites; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics; D003545:Cysteine / Q000737:chemistry; D017931:DNA Primers / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014981:Xenopus / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D017931:DNA Primers; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011347:Procollagen; D011506:Proteins; C054234:chordin; D003545:Cysteine