Crystal structure of a bony fish beta2-microglobulin: insights into the evolutionary origin of immunoglobulin superfamily constant molecules.

Three-dimensional structures of beta(2)-microglobulin (beta2m) from chicken and various mammals have been described previously, but aside from genomic sequences, very little is known about the three-dimensional structures of beta2m in species other than warm-blooded vertebrates. Here, we present the first three-dimensional structure of beta2m from bony fish grass carp (Ctid-beta2m), resolved at 2.1 A. The key structural differences between this new structure and previously published structures are two new hydrogen bonds at positions Ile(37) and Glu(38) in strand C and Lys(66) in strand E, and a hydrophobic pocket around the center of the protein found in Ctid-beta2m. Importantly, Ctid-beta2m has a short D strand and a long loop between stands C and D, rather than the flexible region found in other beta2m structures that serves as a putative binding region for the major histocompatibility complex heavy chain. Comparing the Ctid-beta2m structure with those of bovine and human beta2ms, the Calpha root mean square deviation of the latter are 1.3 A and 1.8 A, respectively. Compared with the constant domains of Lamprey T cell receptor-like receptor (Lamp-TCRLC) and Amphioxus V and C domain-bearing protein (Amphi-VCPC), Ctid-beta2m exhibits very different topology. The three-dimensional structures of domains predicted from Amphi-VCPC/Lamp-TCRLC are distinctly lacking in strand A of beta2ms. There are 18 amino acids at the N terminus of Amphi-VCPC that may have evolved into strand A of beta2ms. A mutation in the BC loops of Amphi-VCPC may have led to the novel topology found in beta2m. Based on these results, Ctid-beta2m may well reflect evolutionary characteristics of ancestral C set molecules.