Zinc, insulin, and the liver: a ménage à trois
Thomas V. O’Halloran, … , Steven J. Philips, Alan D. Attie
Thomas V. O’Halloran, … , Steven J. Philips, Alan D. Attie
Published September 24, 2013
Citation Information: J Clin Invest. 2013;123(10):4136-4139. https://doi.org/10.1172/JCI72325.
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Commentary

Zinc, insulin, and the liver: a ménage à trois

Abstract

Insulin and Zn2+ enjoy a multivalent relationship. Zn2+ binds insulin in pancreatic β cells to form crystalline aggregates in dense core vesicles (DCVs), which are released in response to physiological signals such as increased blood glucose. This transition metal is an essential cofactor in insulin-degrading enzyme and several key Zn2+ finger transcription factors that are required for β cell development and insulin gene expression. Studies are increasingly revealing that fluctuations in Zn2+ concentration can mediate signaling events, including dynamic roles that extend beyond that of a static structural or catalytic cofactor. In this issue of the JCI, Tamaki et al. propose an additional function for Zn2+ in relation to insulin: regulation of insulin clearance from the bloodstream.

Authors

Thomas V. O’Halloran, Melkam Kebede, Steven J. Philips, Alan D. Attie

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Figure 1

Putative Zn2+-binding residues at the IR-insulin interface.

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Putative Zn2+-binding residues at the IR-insulin interface. Model of...
Model of a putative Zn2+-binding site in the insulin-binding site of the IR. The protein coordinates are from the IR-insulin crystal structure (PDB-ID 3W11). Insulin — chains InsA (gold) and InsB (black) are shown — engages with the IR at the αCT (purple). The IR core particle β strands are also shown (light cyan). A Zn2+ ion (transparent sphere) has been modeled in the structure based on the environment and known Zn2+-coordinating abilities of the highlighted residues. IR residues (green sticks) H710 and E706 (from the αCT) and E97 form a putative Zn2+-binding site. A water molecule or InsB side chains can complete the tetracoordinated Zn2+ site after helix rotation/displacement (not shown). Intriguingly, E706 forms a H-bond to a backbone amide on InsB: this docking of the hormone with its receptor could be disrupted by binding of the zinc ion.