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

ABSTRACT: 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 Zn(2+) site on albumin is a 5-coordinate site with average Zn-O/N distances of 1.98 A and a weak sixth O/N bond of 2.48 A, 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 Zn(2+) binding, which induces cooperative allosteric effects related to those of the pH-dependent neutral-to-base transition. N99D and N99H mutations enhance Zn(2+) binding but alter protein stability, whereas mutation of His(67) to alanine removes an interdomain H-bond and weakens Zn(2+) binding. Both wild-type and mutant albumins promote the safe management of high micromolar zinc concentrations for cells in cultures.

SUBMITTER: Blindauer CA 

PROVIDER: S-EPMC2755717 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature