Most blood plasma zinc is bound to albumin, but the structure of the binding site has not been determined. Zn K-edge extended x-ray absorption fine structure spectroscopy and modeling studies show that the major Zn2+ site on albumin is a 5-coordinate site with average Zn-O/N distances of 1.98 Å and a weak sixth O/N bond of 2.48 Å, consistent with coordination to His67 and Asn99 from domain I, His247 and Asp249 from domain II (residues conserved in all sequenced mammalian albumins), plus a water ligand. The dynamics of the domain I/II interface, thought to be important to biological function, are affected by Zn2+ binding, which induces cooperative allosteric effects related to those of the pH-dependent neutral-to-base transition. N99D and N99H mutations enhance Zn2+ binding but alter protein stability, whereas mutation of His67 to alanine removes an interdomain H-bond and weakens Zn2+ binding. Both wild-type and mutant albumins promote the safe management of high micromolar zinc concentrations for cells in cultures. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.
CITATION STYLE
Blindauer, C. A., Harvey, I., Bunyan, K. E., Stewart, A. J., Sleep, D., Harrison, D. J., … Sadler, P. J. (2009). Structure, properties, and engineering of the major Zinc binding site on human albumin. Journal of Biological Chemistry, 284(34), 23116–23124. https://doi.org/10.1074/jbc.M109.003459
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