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Science 321 (5897): 1834-1837

Copyright © 2008 by the American Association for the Advancement of Science

Antigen Recognition by Variable Lymphocyte Receptors

Byung Woo Han,1,2 Brantley R. Herrin,3 Max D. Cooper,3 Ian A. Wilson1,2*

Abstract: Variable lymphocyte receptors (VLRs) rather than antibodies play the primary role in recognition of antigens in the adaptive immune system of jawless vertebrates. Combinatorial assembly of leucine-rich repeat (LRR) gene segments achieves the required repertoire for antigen recognition. We have determined a crystal structure for a VLR-antigen complex, VLR RBC36 in complex with the H-antigen trisaccharide from human blood type O erythrocytes, at 1.67 angstrom resolution. RBC36 binds the H-trisaccharide on the concave surface of the LRR modules of the solenoid structure where three key hydrophilic residues, multiple van der Waals interactions, and the highly variable insert of the carboxyl-terminal LRR module determine antigen recognition and specificity. The concave surface assembled from the most highly variable regions of the LRRs, along with diversity in the sequence and length of the highly variable insert, can account for the recognition of diverse antigens by VLRs.

1 Department of Molecular Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
2 Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA 92037, USA.
3 Emory Vaccine Center and Department of Pathology and Laboratory Medicine, Emory University, 1462 Clifton Road NE, Atlanta, GA 30322, USA.

* To whom correspondence should be addressed. E-mail: wilson{at}

Chronic Lymphocytic Leukemia Monitoring with a Lamprey Idiotope-Specific Antibody.
H. Nakahara, B. R. Herrin, M. N. Alder, R. Catera, X.-J. Yan, N. Chiorazzi, and M. D. Cooper (2013)
Cancer Immunology 1, 223-228
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Definition of a third VLR gene in hagfish.
J. Li, S. Das, B. R. Herrin, M. Hirano, and M. D. Cooper (2013)
PNAS 110, 15013-15018
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Recognition of the Thomsen-Friedenreich Pancarcinoma Carbohydrate Antigen by a Lamprey Variable Lymphocyte Receptor.
M. Luo, C. A. Velikovsky, X. Yang, M. A. Siddiqui, X. Hong, J. J. Barchi Jr., J. C. Gildersleeve, Z. Pancer, and R. A. Mariuzza (2013)
J. Biol. Chem. 288, 23597-23606
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Organization of lamprey variable lymphocyte receptor C locus and repertoire development.
S. Das, M. Hirano, N. Aghaallaei, B. Bajoghli, T. Boehm, and M. D. Cooper (2013)
PNAS 110, 6043-6048
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Lamprey Variable Lymphocyte Receptors Mediate Complement-Dependent Cytotoxicity.
F. Wu, L. Chen, X. Liu, H. Wang, P. Su, Y. Han, B. Feng, X. Qiao, J. Zhao, N. Ma, et al. (2013)
J. Immunol. 190, 922-930
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Highly Dynamic Exon Shuffling in Candidate Pathogen Receptors ... What if Brown Algae Were Capable of Adaptive Immunity?.
A. Zambounis, M. Elias, L. Sterck, F. Maumus, and C. M. M. Gachon (2012)
Mol. Biol. Evol. 29, 1263-1276
   Abstract »    Full Text »    PDF »
Design of a binding scaffold based on variable lymphocyte receptors of jawless vertebrates by module engineering.
S.-C. Lee, K. Park, J. Han, J.-j. Lee, H. J. Kim, S. Hong, W. Heu, Y. J. Kim, J.-S. Ha, S.-G. Lee, et al. (2012)
PNAS 109, 3299-3304
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Identification of a third variable lymphocyte receptor in the lamprey.
J. Kasamatsu, Y. Sutoh, K. Fugo, N. Otsuka, K. Iwabuchi, and M. Kasahara (2010)
PNAS 107, 14304-14308
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Alternative Adaptive Immunity in Jawless Vertebrates.
B. R. Herrin and M. D. Cooper (2010)
J. Immunol. 185, 1367-1374
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A structural basis for antigen recognition by the T cell-like lymphocytes of sea lamprey.
L. Deng, C. A. Velikovsky, G. Xu, L. M. Iyer, S. Tasumi, M. C. Kerzic, M. F. Flajnik, L. Aravind, Z. Pancer, and R. A. Mariuzza (2010)
PNAS 107, 13408-13413
   Abstract »    Full Text »    PDF »
Regulation of antigen-receptor gene assembly in hagfish.
N. Kishishita, T. Matsuno, Y. Takahashi, H. Takaba, H. Nishizumi, and F. Nagawa (2010)
EMBO Rep. 11, 126-132
   Abstract »    Full Text »    PDF »
High-affinity lamprey VLRA and VLRB monoclonal antibodies.
S. Tasumi, C. A. Velikovsky, G. Xu, S. A. Gai, K. D. Wittrup, M. F. Flajnik, R. A. Mariuzza, and Z. Pancer (2009)
PNAS 106, 12891-12896
   Abstract »    Full Text »    PDF »
Plasticity of the immunoglobulin domain in the evolution of immunity.
J. P. Cannon (2009)
Integr. Comp. Biol. 49, 187-196
   Abstract »    Full Text »    PDF »

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