Stephen Berezenko

Novozymes (United Kingdom)

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Peter J. Sadler

University of Warwick

Claudia A. Blindauer

University of Warwick

Alan J. Stewart

University of St Andrews

Darrell Sleep

Albumedix (United Kingdom)

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In-Q-Tel

University of Warwick

Coventry (United Kingdom)

Chinese Academy of Sciences

University of Edinburgh

Nanjing Normal University

University of Hong Kong

Universitat de Barcelona

Warwick Hospital

Indian Institute of Technology Kanpur

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Interdomain zinc site on human albumin

Proceedings of the National Academy of Sciences (2003)

Alan J. Stewart Claudia A. Blindauer Stephen Berezenko Darrell Sleep Peter J. Sadler

Albumin is the major transport protein in blood for Zn 2+ , a metal ion required for physiological processes and recruited by various drugs and toxins. However, the Zn 2+ -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 H 2 O, 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 111 Cd NMR as a probe for Zn 2+ binding to recombinant human albumin. We show that His-67 → Ala (His67Ala) mutation strongly perturbs Cd 2+ 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 Cd 2+ was demonstrated. Cd 2+ 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.

Human serum albumin

Serum Albumin

10.1073/pnas.0436576100

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