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Structure, properties, and engineering of the major zinc binding site on human albumin

Research output: Contribution to journalArticlepeer-review

DOI

Author(s)

CA Blindauer, I Harvey, KE Bunyan, Alan James Stewart, D Sleep, David James Harrison, S Berezenko, PJ Sadler

School/Research organisations

Abstract

Most blood-plasma zinc is bound to albumin, but the structure of the binding site has not been determined. Zn K-edge EXAFS spectroscopy and modeling studies show that the major Zn site on albumin is 5-coordinate with average Zn-O/N distances of 1.98 Angstroms and a weak 6th O/N bond of 2.48 Angstroms, 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 (N-to-B) transition. N99D/H mutations enhance Zn 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.
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Details

Original languageEnglish
Pages (from-to)23116-23124
Number of pages9
JournalJournal of Biological Chemistry
Volume284
DOIs
Publication statusPublished - 21 Aug 2009

    Research areas

  • Human-serum-albumin, Nuclear-magnetic-resonance, To-base transition, Crystal-structure, Metal-binding, Conformational-change, Equilibrium dialysis, In-vitro, Protein, Acid

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