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3D Structure of Human Serum Albumin
On this page, you can see two Human Serum Albumin (HSA) proteins complexed together as they would be in the human bloodstream. While it spins, notice that the protein assembles into a heart-shaped molecule.
Reset and spin this HSA molecule complex.
Look at the secondary structure of HSA. Roughly 67% of HSA is composed of alpha helices, with the remainder of the molecule in turns and extended polypeptides.
Notice the yellow disulfide bridges within the HSA protein that are conserved in all serum albumin orthologs. HSA has 17 interhelical, crosslinking disulfide bridges. These disulfide bridges, formed from Cys-Cys interactions (red), play a large role in creating the loop-link-loop structures and uniting the three structurally homologous domains.
Now, let's look at these three domains of HSA: Domain I (residues 1-195; red), II (residues 196-383; purple), and III (residues 384-585; green). Each of the three highly conserved domains is divided into two subdomains, A and B, which have different binding capacitites.
What is unique about the domains and their subdomains? Each subdomain forms a hydrophobic pocket where fatty acids and other water-insoluble molecules can bury their carbon-rich tails safely away from the surrounding water environment. HSA can then transport the fatty acids throughout the body to their target organs.
Where do these fatty acids bind? Look at the binding sites for palmitic acid (white) in the different domains. These residues are important binding sites for other long-chain fatty acids as well.
Have you ever taken ibuprofen or aspirin for fever or aches? HSA has an exceptional binding capacity for hydrophobic ligands, including many over-the-counter medications. Most of these ligands bind more or less equally in both Domain IIA and IIIA.
Let's look at the amino acids in the IIIA binding pocket that interact with the hydrophobic portions of ibuprofen and aspirin.
The lone tryptophan residue (Trp214) plays an important structural role in the formation of the IIA binding site by limiting the solvent accessibility.
Residue Cysteine 34, located in a loop within Domain I between the second and third alpha helices, is the only cysteine residue that does not participate in any disulfide bridges. Instead, this free sulfhydryl group can form intermolecular disulfide linkages. In addition, Cys34 can form complexes with various mercurial and gold compounds.
In humans, free heme within the blood stream can become toxic as it is oxidized to its ferric state of hemin. Luckily, HSA has a high affinity for hemin and scavenges the molecule from the blood. There is a single binding site for hemin in Domain IB within a narrow hydrophobic cavity.
Look where the Fe3+ molecule in hemin binds to HSA.
--Choi JK, HO J, Curry S, Qin D, Bittman R, Hamilton JA. Interactions of very long-chain saturated fatty acids with serum albumin. Journal of Lipid Research 2002; 43: 1000-1010.
--Dockal M, Carter DC, Ruker F. The three recombinant domains of human serum albumin: structural characterization and ligand binding properties. The Journal of Biological Chemistry 1999; 274: 29303-29310.
--Sugio S, Kashima A, Mochizuki S, Noda M, Kobayashi K. Crystal structure of human serum albumin at 2.5 A resolution. Protein Engineering 1999; 12: 439-446.
--Zunszain PA, Ghuman J, Komatsu T, Tsuchida E, Curry S. Crystal strutural analysis of human serum albumin compexed with hemin and fatty acid. BMC Structural Biology 2003; 3: 6.
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