Although studies suggesting an adaptive immune system in the evolutionary distant jawless vertebrates were conducted almost 50 years ago (Finstad and Good, 1964), Selleckchem Proteasome inhibitor the molecular components of the agnathan adaptive immune system were discovered only recently (Pancer et al., 2004). Sequence

analyses of transcripts expressed by lymphocyte-like cells of sea lamprey larvae immunized with a cocktail of plant mitogens and particulate antigens led to the discovery of the variable lymphocyte receptor (VLR) B genes, which encode antigen receptors in jawless vertebrates. VLRA and VLRC genes were described in subsequent studies (Rogozin et al., 2007, Guo et al., 2009 and Kasamatsu et al., 2010), accentuating the complexity of the adaptive immune system of jawless vertebrates. Unlike mammalian antibodies which use the immunoglobulin-fold

as basic structural unit and are composed of individual heavy and light chains, VLR antibodies are decameric protein complexes generated by iteration of a single polypeptide chain containing beta-sheet forming leucine-rich repeats (LRR) as basic structural units (Pancer et al., 2004). An incomplete VLR gene in germline configuration is flanked by a large number of LRR cassettes, which are copied into the maturing Venetoclax VLR gene by a gene conversion-like process (Alder et al., 2005 and Rogozin et al., 2007). The mature VLR gene consists of a signal peptide, a capping N-terminal LRR, followed by a conserved LRR1 unit, 1–9 variable LRRv units, a capping C-terminal LRR unit and a stalk region, the latter being necessary for cell surface expression of the VLR antibody and for multimerization of the secreted gene product (Pancer et Ergoloid al., 2004 and Herrin and Cooper, 2010). Our initial studies on monoclonal VLR antibodies demonstrated the high degree of specificity with which VLR antibodies detect their antigen (Herrin et al., 2008). This specificity is in accordance with a combinatorial VLR repertoire predicted to exceed 1014 individual antibody sequences (Rogozin et al., 2007). Structural

analyses of three monoclonal VLR antibodies complexed to their respective antigens revealed a solenoid shape of the individual VLR unit with the antigen interacting region located at the inner concave surface of the protein (Han et al., 2008, Velikovsky et al., 2009 and Kirchdoerfer et al., 2012). Importantly, the antigen also makes contact with residues located in a flexible and highly variable loop structure that protrudes from the capping C-terminal LRR unit. In the first solved structure, the VLR antibody forms a pocket for the comparatively small erythrocyte H-trisaccharide antigen between the relatively rigid parallel beta-sheets of the VLR backbone and the flexible C-terminal loop sequences (Han et al., 2008).