Structural origins of hemostasis and adaptive immunity

AbstractEssentials Structural similarities between platelet GPIb and immune proteins of jawless fishes are profiled. VLRs from lamprey eels and hagfish share a conserved domain arrangement with platelet GPIb. Leucine‐rich repeats flanked by disulfide loops are common between glycoprotein Ib and VLRs. Ancestors of the vertebrate lineage likely contain an ancient domain for hemostasis and immunity.Background Adaptive immunity in jawless fishes is performed by a unique set of proteins termed variable lymphocyte receptors ( VLR s). Here we compare the crystallographic structures of VLR s and the human primary hemostasis receptor, glycoprotein ( GP ) Ib. It has been estimated jawless fish vertebrates diverged from jawed vertebrates 500 million years ago. Identifying structural similarities provides insights into the origins of primary hemostasis and the unique adaptive immunity of jawless fishes. Methods Three‐dimensional structures obtained from crystallographic data and primary sequences alignments are compared. The results focus on overall domain arrangement to include the structural roles of leucine‐rich repeats ( LRR s), disulfide bond, and disulfide loop arrangements. Results The crystal structures of human GPI b ( GPI bαN) and jawless fish VLR s are made up of three common segments each. The N‐terminal cap and the C‐terminal cap are characterized by disulfide bonds conserved in both GPI bαN and VLR s. The body of each molecule consists of LRR s which varies depending on the number of LRR s present in each molecule. The stacking of the LRR s results in the formation of a concave surface which serves as a motif to build ligand‐binding specificity with the flanking regions. Conclusion A comparison of VLR and GPI b structures reveals a phylogenetic trail of cellular differentiation contributing to mammalian hemostasis and jawless fish adaptive immunity. The results provide a structural basis to explain some of the interrelationships between hemostasis and immunity in vertebrates and potentially identifies a common ancestral motif linking hemostasis and immunity.