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Zinc deficiency was found to be associated with different diseases, including cancers, but the actual mechanism behind the relation between zinc deficiency and these diseases was not known before.
According to a recent study carried out by an associate professor of the Biological Sciences at Rensselaer Polytechnic Institute (who is a member of the Center for Biotechnology and Interdisciplinary Studies), Hedgehog is a signaling protein, critical to the normal development. It controls cell growth and proliferation that helps to establish the body plan of all animals with bilateral symmetry.
In the Hedgehog signaling pathway, the Hedgehog precursor protein divides itself into two parts and these are the Hedgehog ligand responsible for the signaling and a catalytic domain which is responsible for the self-cleavage. Therefore, no external catalyst is required in this autoprocessing reaction because the Hedgehog catalytic domain is acting as a catalyst for this transformation.
Wang said; there is a link between zinc deficiency and activation of the Hedgehog signaling pathway in many diseases. A paper published on the relation of zinc deficiency and activation of the Hedgehog pathway in the Journal of Biological Chemistry (JBC) by these researchers reveals that zinc inhibits the activation of the Hedgehog signaling pathway by binding the upstream signaling molecule of the Hedgehog pathway.
Researchers also demonstrated that when zinc is present, it binds to the active site of the catalytic domain and inhibits the auto-processing of the Hedgehog precursor protein. The blocked catalytic domain is, therefore, unable to produce the hedgehog ligand and this Hedgehog signaling pathway is blocked. However, if there is no zinc (in the case of zinc deficiency) then there is nothing to inhibit the catalytic domain.
This leads to the production of the Hedgehog ligand and thus, the Hedgehog signaling pathway is turned on. It is also found that there is a correlation between zinc deficiency and Hedgehog signaling pathways like zinc deficiency in autism, cancers like prostate cancer. However, the exact relationship is not fully understood.
As Wang said, in adults, zinc inhibits the production of the Hedgehog ligand and thus, inhibits the Hedgehog signaling pathway. However, the Hedgehog pathway can be activated in zinc-deficient conditions because there is no zinc to inhibit the catalytic domain allowing for the continuous production of the Hedgehog ligand. This is something new that has never been found before.
Researchers examined the interaction of the zinc and the Hedgehog catalytic domain using NMR studies of the astrocytes in vitro; they found the specific amino acids within the catalytic domain responsible for the binding of a zinc-binding.
Reference: Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation. Jian Xie et al. Journal of Biological Chemistry (2015): Link>>