Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.

The Journal of Biological Chemistry
Jian XieChunyu Wang

Abstract

Zinc is an essential trace element with wide-ranging biological functions, whereas 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 2 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 isothermal titration calorimetry 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.

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Citations

Aug 17, 2016·Journal of the American Chemical Society·Jian XieChunyu Wang
Oct 17, 2015·Cancers·Brian P Callahan, Chunyu Wang
Jan 10, 2018·Frontiers in Genetics·Juan A Navarro, Stephan Schneuwly
Jan 24, 2019·Chemical Communications : Chem Comm·Daniel A CiullaBrian P Callahan
Sep 13, 2017·Scientific Reports·Amira JabraniValérie Biou

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