Properties of human serum albumin and albumin atomic coordinates

Human serum albumin is a single-chain protein synthesized in and secreted from liver cells. Normally, it is a simple protein, i.e., it lacks prosthetic groups and covalently bound carbohydrate and lipid. The protein has 585 amino acids and a molecular mass of 66,500 Da; the amino acid sequence has been published by Minghetti, P.P., Ruffner, D.E., Kuang, W.J., Dennison, O.E., Hawkins, J.W., Beattie, W.G. & Dugaiczyk, A. (1986). Molecular structure of the human albumin gene is revealed by nucleotide sequence within q11-22 of chromosome 4. J. Biol. Chem. 261, 6747-6757.
Due to a large number of acidic (98 Glu + Asp) and basic residues (83 Lys + Arg), the protein is highly soluble in aqueous media. Thus, its concentration in blood plasma is ca. 0.6 mM (4% w/w), but solutions of 20% (w/w) can be made for clinical use. The protein is an acidic one, and its net charge is ca. ‒15 at physiological pH, a fact that renders albumin important for the Donnan effect in the capillaries.
Because of its high intravascular concentration, one of albumin’s principal functions is to support the oncotic pressure, which aids in keeping the blood within the circulation. Due to its many titrable amino acid residues, albumin has a significant buffering capacity. It is also an important circulating antioxidant and has enzymatic properties.
According to X-ray crystallographic analyses of human serum albumin and its recombinant version, the polypeptide chain forms a heart-shaped protein with approximate dimensions of 80×80×80 Å and a thickness of 30 Å. It has about 67% α-helix but no β-sheet and can be divided into three homologous domains (I-III), and each of these is comprised of two subdomains (A and B). The A and B subdomains have six and four α-helices, respectively, connected by flexible loops. The principal regions of ligand binding to human serum albumin are located in cavities in subdomains IIA and IIIA, which are formed mostly of hydrophobic and positively charged residues and exhibit similar chemistry. All but one of the 35 cysteine residues are involved in the formation of 17 stabilizing disulfide bonds (He X.M. & Carter, D.C. (1992). Atomic structure and chemistry of human serum albumin. Nature 358, 209–215; Sugio, S., Kashima, A., Mochizuki, S., Noda, M. & Kobayashi, K. (1999). Crystal structure of human serum albumin at 2.5 A resolution. Protein Eng. 12, 439-446). The crystal structure of human serum albumin without and with ligands, including biologically important molecules such as fatty acids and drugs, or complexed with other proteins, can be seen at the link (Universal Protein Resource Knowledgebase) or (Worldwide Protein Data Bank). Small-angle X-ray scattering studies of albumin in solution show general agreement with the crystal structure. Also, a combined phosphorescence depolarization-hydrodynamic modeling study has suggested that the overall conformation of albumin in neutral solution is very similar to that observed in crystal structures.

The canonical structure of the molecule, supported by the conserved set of disulfide bridges, is maintained in all mammalian serum albumins and any changes in sequence are highly correlated with evolution of the species. Recently, the determination of the structures of bovine, horse, rabbit, equine and leporine albumins revealed in some cases different amino-acid compositions and conformations of the binding pockets in comparison to the human molecule; however, much more significant differences were observed on the surface of the proteins (Majorek, K.A., Porebski, P.J., Dayal, A., Zimmerman, M.D., Jablonska, K., Stewart, A.J., Chruszcz, M. & Minor, W. (2012). Structural and immunologic characterization of bovine, horse, and rabbit serum albumins. Mol. Immunol. 52, 174–182; Bujacz, A. (2012). Structures of bovine, equine and leporine serum albumin. Acta Crystallogr. D Biol. Crystallogr. 68, 1278–1289).