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Plasma metalloproteins

Latest update: At last (!!): Crystallographic evidence for the major zinc binding site in human (and horse) blood plasma: Circulatory zinc transport is controlled by distinct interdomain sites on mammalian albumins.

One of the many compartments in biological systems which are involved in metal ion homeostasis is the blood plasma of vertebrates.

It is for example known that the zinc concentration in human blood is ca. 10-20 micromolar. The largest part (about three quarters) of plasma Zn(II) is bound by human serum albumin, which is present at a concentration of ca. 600 micromolar - it is thus the most abundant protein in plasma. Besides its likely, but not well understood role in zinc homeostasis, albumin performs many functions; in particular, it is resposible for the transport of fatty acids, bilirubin, and many xenobiotics including drugs.

Together with Dr. Alan Stewart and Prof. Peter Sadler, we have previously discovered the location of the high-affinity zinc-binding site on human albumin (see: Interdomain zinc site on human albumin). Intriguingly, the site lies at the interfact between two domains:

alb_Zn

 

The image shows the predicted structure of the high-affinity zinc site on human albumin. Domain I is shown in orange, and domain II in blue, the zinc zinc ion is shown in purple. Besides two histidine residues, an aspartate, an asparagine, and an external ligand such as a water molecule were modelled to coordinate the zinc ion.

For an update on the zinc site structure in albumin crystals see the link at the top of the page.

Albumin_fat

 

The major zinc site is adjacent to one of several binding sites for fatty acids, and we have hypothesised that the binding of fatty acids and zinc to its major site may be mutually exclusive. This potential allosteric mechanism may mediate zinc signals in the blood.

This has been verified experimentally (in vitro): A Molecular Mechanism for Modulating Plasma Zn Speciation by Fatty Acids. Possible downstream effects are explored together with Dr. Alan Stewart (University of St Andrews) in Plasma free fatty acid levels influence Zn2+-dependent histidine-rich glycoprotein–heparin interactions via an allosteric switch on serum albumin.

Allosteric binding of metals and fatty acids is also the molecular mechanism that underlies a diagnostic test for early detection of heart attacks: Allosteric Inhibition of Cobalt Binding to Albumin by Fatty Acids: Implications for the Detection of Myocardial Ischemia .

Further work, in collaboration with Dr. Alan Stewart (University of St Andrews), is ongoing.

 

For further reading, see our reviews in Biochemical Society Transactions, BBA, and Current Trends in Medicinal Chemistry, and the two papers Structure, Properties, and Engineering of the Major Zinc Binding Site on Human Albumin and Plasma fatty acid levels may regulate the Zn2+-dependent activities of histidine-rich glycoprotein.

Also see:

Jin Lu's homepage

Esther Martin's homepage