Multistep molecular mechanism for bone morphogenetic protein extracellular transport in the Drosophila embryo.
In the Drosophila embryo, formation of a bone morphogenetic protein (BMP) morphogen gradient requires transport of a heterodimer of the BMPs Decapentaplegic (Dpp) and Screw (Scw) in a protein shuttling complex. Although the core components of the shuttling complex--Short Gastrulation (Sog) and Twisted Gastrulation (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/Scw 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 evolutionarily 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.
Faculty of Life Sciences,  University of Manchester, Manchester M13 9PT,  United Kingdom.
Annick
A
Sawala
Catherine
C
Sutcliffe
Hilary L
HL
Ashe
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D024141:Collagen Type IV / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004330:Drosophila / Q000166:cytology*; D029721:Drosophila Proteins / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D005775:Gastrula / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D005982:Glutathione Transferase / Q000378:metabolism; D008024:Ligands; D008969:Molecular Sequence Data; D011487:Protein Conformation; D021381:Protein Transport; D017386:Sequence Homology, Amino Acid
D019485:Bone Morphogenetic Proteins; D024141:Collagen Type IV; D029721:Drosophila Proteins; D008024:Ligands; C064196:dpp protein, Drosophila; D005982:Glutathione Transferase