Featured Article - August 2012
Short description: Serum albumin is an abundant plasma protein that can cause allergic reactions. The crystal structures of bovine, horse and rabbit serum albumin now provide insight into these properties.
Serum albumin (SA) is the most abundant protein in mammalian plasma, reaching a concentration of ca. 0.6mM. SA maintains the osmotic pressure in plasma and also serves as a carrier for myriad ligands, including metabolites, nutrients, fatty acids and ions such as Ca2+ and Mg2+. SAs of animal origin share ca. 60% identity with human SA (HSA). Despite this high degree of similarity, animal SAs can be allergenic, with IgE antibodies showing cross-reactivity to different species' SAs — a feature with considerable clinical implications. For example, a person with an allergy to bovine SA (present in cow's milk and meat) could have an allergic reaction to dog or cat dander (which also contains SA) without ever being exposed to the latter antigens.
Several structures of HSA have been published, but not those of other animals. In order to understand the differences between HSA and other mammalian orthologs, and the basis for allergic responses to the latter, Minor, Chruszcz and colleagues (PSI NYSGRC) solved bovine (BSA), equine (ESA) and rabbit (RSA) SA crystal structures. BSA is a major allergen in bovine meat, whereas ESA and RSA can cause allergic reactions by inhalation. This work allows the comparison of these animal SAs to HSA and provides a structural context within which to understand their antigenic properties.
The structures of animal SAs are overall quite similar to HSA, with an average root-mean-square deviation of 1.1–1.2 Å. The heart-shaped protein is formed by three domains (I, II, III), each divided into two subdomains (A and B). Of note, the BSA structure showed three ordered Ca2+ ions bound within domain I — though Ca2+ binding to SA had been previously studied, the exact location of the binding sites was unknown. The ESA and RSA structures contained a number of unidentified ligands, including one bound to a site that had not been previously observed in HSA.
Finally, by mapping the regions or residues known to be involved in antigenicity of the different SAs onto the structures, the authors could define potential epitopes and understand the basis for cross-reactivity by considering the surface exposure of those residues and their conservation among SAs. For BSA, previously well characterized in immunological studies, such analysis highlighted two main regions with considerable differences to HSA, both on subdomain IB; other regions (in the loop connecting IIA and IIB, and in IIIA and IIB) can also contribute to the antigenicity of BSA.
K.A. Majorek et al. Structural and immunologic characterization of bovine, horse, and rabbit serum albumins.
Mol Immunol. 52, 174-182 (2012). doi:10.1016/j.molimm.2012.05.011