title: Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.
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.
authors: From the Biochemistry and Biophysics Graduate Program, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors: Jian
authors: J
authors: Xie
authors: Department of Chemistry, Binghamton University, Binghamton, New York 13902, and.
authors: Timothy
authors: T
authors: Owen
authors: Department of Chemistry and Chemical Biology.
authors: Ke
authors: K
authors: Xia
authors: Department of Biomedical Engineering, and.
authors: Ajay Vikram
authors: AV
authors: Singh
authors: Department of Biological Sciences.
authors: Emiley
authors: E
authors: Tou
authors: Department of Chemistry and Chemical Biology.
authors: Lingyun
authors: L
authors: Li
authors: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180.
authors: Brigitte
authors: B
authors: Arduini
authors: Wadsworth Center, New York State Department of Health, Albany, New York 12208.
authors: Hongmin
authors: H
authors: Li
authors: Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, Department of Biomedical Engineering, and.
authors: Leo Q
authors: LQ
authors: Wan
authors: Department of Chemistry, Binghamton University, Binghamton, New York 13902, and.
authors: Brian
authors: B
authors: Callahan
authors: From the Biochemistry and Biophysics Graduate Program, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, Department of Chemistry and Chemical Biology, Department of Biological Sciences, wangc5@rpi.edu.
authors: Chunyu
authors: C
authors: Wang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D020134:Catalytic Domain; D029721:Drosophila Proteins / Q000235:genetics; D053823:Hedgehog Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D051381:Rats; D013816:Thermodynamics; D015032:Zinc / Q000172:deficiency* / Q000494:pharmacology*
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D015032:Zinc
keywords: Cancer; Hedgehog Autoprocessing; Hedgehog Signaling Pathway; Isothermal Titration Calorimetry (ITC); Nuclear Magnetic Resonance (NMR); Zinc