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Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen

Abstract

Variable lymphocyte receptors (VLRs) are leucine-rich repeat proteins that mediate adaptive immunity in jawless vertebrates. VLRs are fundamentally different from the antibodies of jawed vertebrates, which consist of immunoglobulin (Ig) domains. We determined the structure of an anti–hen egg white lysozyme (HEL) VLR, isolated by yeast display, bound to HEL. The VLR, whose affinity resembles that of IgM antibodies, uses nearly all its concave surface to bind the protein, in addition to a loop that penetrates into the enzyme active site. The VLR–HEL structure combined with sequence analysis revealed an almost perfect match between ligand-contacting positions and positions with highest sequence diversity. Thus, it is likely that we have defined the generalized antigen-binding site of VLRs. We further demonstrated that VLRs can be affinity-matured by 13-fold to affinities as high as those of IgG antibodies, making VLRs potential alternatives to antibodies for biotechnology applications.

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Figure 1: Structure of the VRLB.2D–HEL complex and comparison with antibody–HEL complexes.
Figure 2: Comparison of ligand recognition by LRR family proteins.
Figure 3: Surface analysis of VLR-HEL and antibody-HEL binding interfaces.
Figure 4: The VLRB.2D–HEL binding interface.
Figure 5: Molecular architecture of the antigen-binding site of VLRs.

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Acknowledgements

This study was supported by the US National Institutes of Health (AI065612 and AI036900 to R.A.M.) and the US National Science Foundation (MCB-0614672 to Z.P.). R.A.M. and Z.P. were also supported by an Intercenter Collaboration Grant from the University of Maryland Biotechnology Institute. We thank H. Robinson (Brookhaven National Synchrotron Light Source) for X-ray data collection. Support for beamline X29 comes from the Offices of Biological and Environmental Research and of Basic Energy Sciences of the US Department of Energy, and from the National Center for Research Resources of the National Institutes of Health. L.M.I. and L.A. were supported by the National Library of Medicine of the National Institutes of Health. L.D. is supported by the Cancer Research Institute.

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Correspondence to Zeev Pancer or Roy A Mariuzza.

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Velikovsky, C., Deng, L., Tasumi, S. et al. Structure of a lamprey variable lymphocyte receptor in complex with a protein antigen. Nat Struct Mol Biol 16, 725–730 (2009). https://doi.org/10.1038/nsmb.1619

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