Human Serum Albumin

Human Serum Albumin (HSA) is a versatile transporter protein. Its primary function is to carry fatty acids around the blood-stream. This page shows how the protein binds long-chain fatty acid ligands. If you get lost at any stage, press the Reset button at the bottom of this section. If that doesn't work, just reload the page in your browser to restart.

Overview of the protein structure
The protein is composed of a single polypeptide chain. It is 67% alpha-helical and contains no beta-sheet structure. The N and C termini are indicated.

  HSA contains three homologous (i.e. similar) domains, labelled I, II and III. In this view they are coloured red , green, and blue respectively.

Fatty acid structure

Fatty acids have a hydrophobic ("water-hating") methylene tail and a hydrophilic ("water-loving") carboxylate head-group which carries a net negative charge at physiological pH. In the figures below, carbon atoms are grey, oxygens are red and hydrogen atoms are not shown.

  Space-filling representation.

  Stick representation.

Because of their hydrophobic tails, long-chain fatty acids are only sparingly soluble in water. The role of HSA molecules, which can each bind several molecules of fatty acid, and are present in blood plasma at about 0.6 mM, is to increase the capacity of the circulatory system to carry fatty acids.

How does HSA bind fatty acids?

The protein binds at least five fatty acid molecules. Shown here is the structure of HSA complexed with myristic acid.

  Although the three domains are similar in structure to one another, the disposition of fatty acid binding sites is different for each domain. For example, domain I contains one complete binding site, whereas domain III has three.

  Let us concentrate just on the fatty acid molecule bound to domain I.

  The fatty acid molecule is bound just to the C-terminal half of this domain.

  Now focus on that part of domain I which forms the fatty acid binding site. The view is rotated by about 90 degrees from that shown above.

  The hydrophobic binding pocket for fatty acid in domain I. All the non-hydrogen atoms are shown; hydrophobic residues are coloured green (other residues are red). The methylene tail of the fatty acid is encapsulated by in a hydrophobic pocket.

  Same view as above but with the fatty acid shown in stick representation so that you can see the hydrophobic interior of the pocket.

  Space-filling representation of the fatty acid with stick representation of the protein.

  The negatively charged carboxylate head-group of the fatty acid is close to the surface of the protein. It makes an electrostatic "salt- bridge" interaction with Arg117. Note how close the positively charged end of the Arg side-chain is to the fatty acid carboxylate. The position of Arg 117 is stabilised by a negatively charged side-chain, Asp183. These two side-chains are coloured according to atom-type ( red - oxygen; blue - nitrogen; grey - carbon).

  The surface of HSA is very hydrophilic. Hydrophilic residues are coloured blue, hydrophobic residues in green. This makes the protein very soluble in water. Thus HSA forms a hydrophilic "wrapper" for the very hydrophobic fatty acid molecules and solubilizes them in blood serum.

Conformational changes

  When fatty acids bind to HSA, the protein undergoes a large conformational change. The structure of HSA with no fatty acid bound is shown in white. The HSA-fatty acid complex with shown with the three domains coloured red, green and blue. Domains I and III both move relative to domain II. The reason for the conformational change is not yet understood. However, this does show that proteins are not static structures!

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