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Proteins are a chain of linked amino acids that can be grouped into functional units called domains. Usually there are more than one and all parts of a domain are close in order to interact. The catalytic domain is where a chemical reaction takes place. Therefore, the 3D structure of a domain requires proper folding in order to allow a chemical reaction to occur. (ABOVE) Glucose acts to keep a domain either OPEN (functioning) or CLOSED Image Credit: Stack Exchange

How zinc deficiency affects embryo and adults

Zinc deficiency is associated with diseases such as autism, lung cancer, prostate cancer, and ovarian cancer — and can affect the bilateral symmetry in the developing embryo.

The Hedgehog pathway is a key regulator of cell growth and establishes our bilateral body plan. It does the same in all animals. Before the Hedgehog pathway is initiated though, a precursor protein to Hedgehog divides (cleaves) into two parts: (1) the Hedgehog molecule responsible for signaling the bilateral body plan, and (2) a catalytic domain (a pocket or groove where only the correct molecules can attach) that initiates future cleavages of the Hedgehog pathway.

Researchers found that when zinc is present, it binds to the Hedgehog catalytic domain and interfers with the Hedgehog second stage or stops the generation of future cleavages.

"Our paper suggests a link between zinc deficiency and activation of the Hedgehog pathway in many diseases... Hedgehog is critical to normal development, but in adults the pathway, if re-activated, may lead to uncontrolled cell growth and proliferate into cancer."

Chunyu Wang, associate professor, Biological Sciences, Rensselaer Polytechnic Institute, member of the Center for Biotechnology and Interdisciplinary Studies.

So, too little zinc in a prenatal diet can negatively affect a baby's body plan. However as adults, too little zinc can lead to cancers. The work was published in the Journal of Biological Chemistry, demonstrating how zinc inhibits the activation of the Hedgehog signaling pathway by binding to the catalytic domain of the precursor protein and preventing future cleavages.

"Normally, in adults, zinc will inhibit the production of Hedgehog, therefore inhibiting the Hedgehog pathway. But if there is a zinc deficiency, the pathway can be activated due to enhanced production of the Hedgehog process ... Zinc inhibits this autoprocessing, providing an additional mechanism of how zinc deficiency may promote cancer development. Zinc and Hedgehog are essential biomolecules; linking the two has profound implications for normal physiology and disease."

Chunyu Wang PhD

Abstract
Background: In many types of cancers, zinc deficiency and over-production of Hedgehog (Hh) ligand co-exist.

Results: Zinc binds to the active site of the Hedgehog-intein (Hint) domain and inhibits Hh ligand production both in vitro and in cell culture.

Conclusion: Zinc influences the Hh autoprocessing.

Significance: This study uncovers a novel mechanistic link between zinc and the Hedgehog signaling pathway.

Abstract
Zinc is an essential trace element with wide-ranging biological functions, while the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. The upstream activator of Hh signaling, the Hh ligand, originates from Hh autoprocessing, which converts the Hh precursor protein to the Hh ligand. In an in vitro Hh autoprocessing assay, we show that zinc inhibits Hh autoprocessing with a Ki of μM. We then demonstrate that zinc inhibits Hh autoprocessing in a cellular environment with experiments in primary rat astrocyte culture. Solution NMR reveals that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing, and ITC provided the thermodynamics of the binding. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand.

A team of researchers participated in this research, including first author Jian Xie, a fourth-year graduate student in the biochemistry and biophysics graduate program at Rensselaer; the research group of Brian Callahan, assistant professor of chemistry at Binghamton University, at the State University of New York; the group of Leo Wan, assistant professor in the Department of Biomedical Engineering at Rensselaer; and Brigitte Arduini, director of Rensselaer Center for Stem Cell Research in the Center of Biotechnology and Interdisciplinary Studies, among many others.

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