Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 34, Pages 23116-23124Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.003459
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Funding
- Biotechnology and Biological Sciences Research Council
- Novozymes Biopharma, Ltd.
- European Community Marie Curie Fellowship
- Wellcome Trust
- Wolfson Foundation
- Olga Kennard Fellowship from the Royal Society
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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 angstrom and a weak sixth O/N bond of 2.48 angstrom, consistent with coordination to His(67) and Asn(99) from domain I, His(247) and Asp(249) 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 wildtype and mutant albumins promote the safe management of high micromolar zinc concentrations for cells in cultures.
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