Zinc deficiency:Hedgehog activation

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  • Published: May 1, 2015
  • Author: David Bradley
  • Channels: NMR Knowledge Base
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Cancer connection

Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation

Zinc deficiency, which is associated with various cancers, can lead to activation of the "Hedgehog" (Hh) signalling pathway, according to evidence arising from studies that involved solution NMR spectroscopy.

"Hedgehog is critical to normal development, but in adults the pathway, if reactivated, may lead to uncontrolled cell growth and proliferation in cancer,” explains Chunyu Wang, who is associate professor in Biological Sciences at the Rensselaer Polytechnic Institute (RPI) in Troy, New York, USA. "Our paper suggests a link between zinc deficiency and activation of the Hedgehog pathway in many diseases where zinc deficiency and Hedgehog activation co-exist."

Writing in the Journal of Biological Chemistry, Wang and his colleagues Jian Xie, Leo Wan and Brigitte Arduini, together with Brian Callahan's team at Binghamton University and others have demonstrated that zinc inhibits the activation of the Hedgehog signalling pathway by binding to the autoprocessing domain of the precursor protein that converts the precursor to the active Hedgehog ligand.

Critical hedgehog

The Hedgehog pathway is critical to the regulation of cell growth and development and helps generate the bilateral symmetry apparent in the body plans of animals as the embryo grows into a foetus. It is implicated in the development of many cancers - e.g. prostate, lung, ovarian - and as such has been the focus of pharmaceutical companies for many years. One particular critical step that launches Hedgehog signalling, involves the Hedgehog precursor protein dividing, or self-cleaving, into two parts: the Hedgehog ligand that is responsible for signalling, and a catalytic, or autoprocessing, domain that was responsible for the self-cleavage in the first place. No external factors are required for this autoprocessing reaction to take place.

Researchers have demonstrated that the presence of zinc ions leads to inhibition of self cleavage as they bind to the catalytic site. Zinc deficiency has previously been shown to correlate with the emergence of autism and the development of several cancers. For instance, one of the hallmarks of prostate cancer is zinc deficiency in prostate tissue. However, the precise connection between a lack of zinc and the development of disease was not fully understood. The new work offers a molecular underpinning to the disease processes.

Zinc deficiency

"Normally, in adults, zinc will inhibit the production of the Hedgehog ligand, and therefore inhibit the Hedgehog pathway," explains Wang. "But, if there is a zinc deficiency, the pathway can be activated due to enhanced production of Hedgehog ligand. We show that zinc inhibits this autoprocessing reaction from the precursor to the ligand, providing an additional mechanism of how zinc deficiency may promote cancer development. This is something that nobody else has shown before. Zinc and Hedgehog are essential and extremely versatile biomolecules; linking these two will have profound implications for normal physiology and disease."

The study involved the in vitro and cell culture investigation of star-shaped brain cells known as astrocytes. Solution NMR spectroscopy revealed details of the zinc interaction with the Hedgehog autoprocessing domain and to show which specific amino acids within the protein are involved in binding to zinc ions.

Related Links

J Biol Chem 2015, online: "Zinc Inhibits Hedgehog Autoprocessing: Linking Zinc Deficiency with Hedgehog Activation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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