The integrin-binding protein QBRICK holds another integrin ligand in position, Kiyozumi et al. show, suggesting how defects in QBRICK lead to a rare developmental disorder.
Children with the inherited disorder Fraser syndrome suffer from severe, often fatal, birth defects. Mutations in four genes trigger the syndrome. Three of these genes encode proteins, including QBRICK, that localize to the basement membrane between an organ's outer epithelial cells and the mesenchymal cells beneath. During development of an organ such as the kidney, epithelial and mesenchymal cells interact with the basement membrane, and without this interplay the organ can't form properly. For mesenchymal cells, the α8β1 integrin serves as the basement membrane receptor.
Kiyozumi et al. tested whether QBRICK is the binding partner of the α8β1 integrin. Mouse embryos that lacked QBRICK showed reduced binding between the α8β1 integrin and the basement membrane, suggesting that QBRICK and the integrin interlock. However, rodents that carried a version of QBRICK that can't latch onto the integrin were healthy and had normal α8β1 integrin binding, indicating that a direct interaction between the two proteins isn't necessary for development. Instead, the researchers found, QBRICK helps anchor another basement membrane protein, nephronectin, which connects to α8β1 integrin and promotes interactions between mesenchymal cells and the basement membrane.
Mice lacking QBRICK produce normal amounts of nephronectin. But the researchers suspect that without QBRICK to detain them in the basement membrane, the nephronectin molecules become unstable and are destroyed.
