Scientists in the Division of Structural Biology have discovered the structural basis of a crucial interaction between signalling proteins that control aspects of embryonic development, and which may have a role in some cancers.
The 'hedgehog' family of genes (so called because fruitfly embryos with mutations in one of these genes develop spikes all over) produce proteins that diffuse through the embryo and direct the patterning of developing tissues and organs. In vertebrates there are complex controls in this pathway, with a handful of other proteins that either receive the hedgehog signal and pass it into cells, or block its effects.
Christian Siebold and his colleagues focused on one of these, hedgehog interacting protein (HHIP), which sits in the cell membrane and inhibits hedgehog signalling in humans and other vertebrates. HHIP is known to be involved in nerve growth and guidance, and its levels are reduced in some cancers. The researchers used the high-intensity X-ray facilities at the European Synchrotron Radiation Facility and the Diamond Light Source to obtain 3-D structures of the HHIP molecule both on its own and with hedgehog protein bound to it.
They found that HHIP formed the attachment via a zinc ion carried on the vertebrate hedgehog protein, an evolutionary relic that it does not need for its role in activating the hedgehog pathway. 'By exploiting this zinc ion, which is absent in the fruitfly hedgehog protein, vertebrates have gained an extra level of control', says Siebold. They also made and solved structures of the complexed proteins with and without calcium, showing how this metal also increases the affinity between HHIP and hedgehog in a manner that is 'tuneable' through changing levels of calcium.
Mutations in the hedgehog gene that affect the zinc-dependent binding site cause brain abnormalities, facial deformities and some cancers in humans, suggesting that healthy development requires inhibition mediated through this site as a balance to activation. 'Our study suggests how such mutations might disrupt a key control pathway in human development', says Siebold.
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For more information on Dr Siebold's research, click here.