Multistep molecular mechanism for Bone morphogenetic protein extracellular transport in the Drosophila embryo

摘要

In the Drosophila embryo, formation of a bone morphogenetic protein (BMP) morphogen gradient requires transport of a hetero-dimer of the BMPs Decapentaplegic (Dpp) and Screw (Sew) in a protein shuttling complex. Although the core components of the shuttling complex—Short Gastrulation (Sog) and Twisted Gastru-lation (Tsg)—have been identified, key aspects of this shuttling system remain mechanistically unresolved. Recently, we discovered that the extracellular matrix protein collagen IV is important for BMP gradient formation. Here, we formulate a molecular mechanism of BMP shuttling that is catalyzed by collagen IV. We show that Dpp is the only BMP ligand in Drosophila that binds collagen IV. A collagen IV binding-deficient Dpp mutant signals at longer range in vivo, indicating that collagen IV functions to immobilize free Dpp in the embryo. We also provide in vivo evidence that collagen IV functions as a scaffold to promote shuttling complex assembly in a multistep process. After binding of Dpp/ Sew and Sog to collagen IV, protein interactions are remodeled, generating an intermediate complex in which Dpp/Scw-Sog is poised for release by Tsg through specific disruption of a collagen IV-Sog interaction. Because all components are evolutionary conserved, we propose that regulation of BMP shuttling and immobilization through extracellular matrix interactions is widely used, both -during development and in tissue homeostasis, to achieve a precise extracellular BMP distribution.