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Interdomain zinc site on human albumin

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Alan James Stewart, CA Blindauer, S Berezenko, D Sleep, PJ Sadler

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Abstract

Albumin is the major transport protein in blood for Zn2+, a metal ion required for physiological processes and recruited by various drugs and toxins. However, the Zn2+-binding site(s) on albumin is ill-defined. We have analyzed the 18 x-ray crystal structures of human albumin in the PDB and identified a potential five-coordinate Zn site at the interface of domains I and II consisting of N ligands from His-67 and His-247 and O ligands from Asn-99, Asp-249, and H2O, which are the same amino acid ligands as those in the zinc enzymes calcineurin, endonucleotidase, and purple acid phosphatase. The site is preformed in unliganded apo-albumin and highly conserved in mammalian albumins. We have used 111Cd NMR as a probe for Zn2+ binding to recombinant human albumin. We show that His-67 → Ala (His67Ala) mutation strongly perturbs Cd2+ binding, whereas the mutations Cys34Ala, or His39Leu and Tyr84Phe (residues which may H-bond to Cys-34) have no effect. Weak Cl− binding to the fifth coordination site of Cd2+ was demonstrated. Cd2+ binding was dramatically affected by high fatty acid loading of albumin. Analysis of the x-ray structures suggests that fatty acid binding to site 2 triggers a spring-lock mechanism, which disengages the upper (His-67/Asn-99) and lower (His-247/Asp-249) halves of the metal site. These findings provide a possible mechanism whereby fatty acids (and perhaps other small molecules) could influence the transport and delivery of zinc in blood.
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Original languageEnglish
Pages (from-to)3701-3706
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number7
DOIs
Publication statusPublished - 1 Apr 2003

    Research areas

  • Human-serum-albumin, Resolution crystal-structures, Carboxypeptidase-A, Nickel(II) binding

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