We need zinc: one-tenth of the proteins in our cells require this metal for their normal functions in all aspects of cell metabolism.
We acquire zinc by eating it — in foods or multivitamin supplements — but up to 30% of people in some parts of the world are at risk for zinc deficiency, which can cause slowed growth, impaired immune function, neurological disorders and cancers. The World Health Organization considers zinc deficiency a leading contributor to disease and death.
Despite zinc’s critical role, however, it has not been clear how the metal gets put into the hundreds of proteins that use it or how our cells respond to zinc deficiency.
Now, a team led by investigators at Vanderbilt University Medical Center and Indiana University Bloomington has described and characterized the first zinc metallochaperone: a protein that puts zinc into other “client” proteins. The findings, reported in the journal “Cell,” shed light on the public health issue of zinc deficiency and open an entirely new area of biology for exploration.
“Metallochaperones do what the name implies: they chaperone metal nutrients, in this case zinc, to high priority targets, and are put to work by the cell when there is not enough zinc to go around.” said IU’s David Giedroc, Lilly Chemistry Alumni Professor and co-corresponding senior author of the study.
The study describes the zinc metallochaperone, which the researchers — in collaboration with an international gene nomenclature committee — named ZNG1 (for zinc regulated GTPase metalloprotein activator 1).
“This is the first identified protein that puts zinc into other proteins,” said Eric Skaar, Ernest W. Goodpasture professor of pathology, microbiology and immunology at Vanderbilt University Medical Center and co-corresponding senior author of the study. “We think it may be one of the most important regulatory strategies by which humans cope with severe zinc starvation, which is one of the most important public health issues in the world.”
Giedroc, distinguished professor of chemistry, and two members of his group at Indiana University, graduate student Matthew Jordan and senior scientist Katie Edmonds, contributed structural and biochemical studies of ZNG1 sufficient to propose an atomic-level model for how ZNG1 and METAP1 “talk” to one another. Richard DiMarchi, distinguished professor of chemistry at IU, also participated in this study.
The researchers found that ZNG1 is conserved from yeast to humans. Using human, mouse and zebrafish versions of ZNG1 as “bait” to discover ZNG-interacting proteins, they identified the enzyme METAP1 as a client for zinc insertion. METAP1 removes the initial amino acid on about half of newly synthesized proteins, contributing to protein stability, maturation and cellular location.
Mutation of the ZNG1 gene in zebrafish and mouse models caused reduced cellular proliferation and mitochondrial dysfunction — consistent with growth defects observed for zinc deficiency.
Collectively, the biochemical, structural, genetic and pharmacological studies using a variety of model systems demonstrated a critical role for ZNG1 in regulating the cellular zinc economy.
“We think that when the body is starved for zinc, ZNG1 ensures that zinc gets delivered to the most important zinc-containing proteins,” Skaar said. “This opens up an exciting new area of biology, where we have these regulatory factors controlling a number of different physiological processes through metal insertion.”
This research was supported by grants from the National Institutes of Health (AI150701, AI101171, GM118157), the Ernest W. Goodpasture Chair in Pathology, the Lilly Chemistry Alumni Chair and a pilot grant provided by the Vanderbilt-Ingram Cancer Center NIH-funded support grant (CA068485).