Abstract
Jawless vertebrates represented by lampreys and hagfish use variable lymphocyte receptors (VLRs) as antigen receptors to mount adaptive immune responses. VLRs generate diversity that is comparable to immunoglobulins and T-cell receptors by a gene conversion-like mechanism, which is mediated by cytosine deaminases. Currently, three types of VLRs, VLRA, VLRB, and VLRC, have been identified in lampreys. Crystal structures of VLRA and VLRB in complex with antigens have been reported recently, but no structural information is available for VLRC. Here, we present the first crystal structure of VLRC from the Japanese lamprey (Lethenteron japonicum). Similar to VLRA and VLRB, VLRC forms a typical horseshoe-like solenoid structure with a variable concave surface. Strikingly, its N-terminal cap has a long loop with limited sequence variability that protrudes toward the concave surface, which is the putative antigen-binding surface. Furthermore, as predicted previously, its C-terminal cap lacks a highly variable protruding loop that plays an important role in antigen recognition by lamprey VLRA and VLRB. Recent work suggests that VLRC+ lymphocytes in jawless vertebrates might be akin to γδ T cells in jawed vertebrates. Structural features of lamprey VLRC described here suggest that it may recognize antigens in a unique manner.
Highlights
All classes of jawed vertebrates ranging from mammals to the cartilaginous fish employ immunoglobulins (Igs) and T-cell receptors (TCRs) as antigen receptors [1]
Lamprey VLRC is composed of eight modules, including LRRNT, LRR1, LRRV1, LRRV2, LRRV3, LRRVe, connecting peptide (CP) and LRRCT in this order
The concave surface of lamprey VLRC is formed by the bsheet made up of eight b-strands; the b1-strand is anti-parallel whereas the remaining b-strands are arranged in a parallel fashion (Figure 1)
Summary
All classes of jawed vertebrates (gnathostomes) ranging from mammals to the cartilaginous fish employ immunoglobulins (Igs) and T-cell receptors (TCRs) as antigen receptors [1]. VLRs acquire their diversity through rearrangement of leucinerich repeat (LRR) modules [4,5], whereas the recombination of variable (V), diversity (D) and joining (J) gene segments is responsible for the generation of diversity in both B-cell receptors and TCRs [6,7]. Sequence diversity of mature VLRs is generated by the step-wise insertion of an LRRencoding module into the immature, incomplete VLR gene during the development of lymphocytes [8,9]. This assembly of VLR genes is thought to occur through a gene conversion-like mechanism mediated by cytosine deaminases of the AID-APOBEC family [10,11]
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