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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 Han1,2, Brantley R. Herrin3, Max D. Cooper3, and Ian A. Wilson1,2*

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.

Figure 1 Fig. 1.. Overall architecture of the VLR RBC36-ECD in complex with the H-trisaccharide. (A) Schematic diagram of RBC36. Regions from left to right: signal peptide (SP), N-terminal LRR (LRRNT), five variable LRRs (LRR1, LRRVs), connecting peptide (CP), C-terminal LRR (LRRCT), threonine/proline-rich stalk region, GPI anchor, and hydrophobic tail. (B) Ribbon diagram of RBC36-ECD in complex with H-trisaccharide. LRRNT, LRRs, and LRRCT are colored blue, green, and red, respectively. Carbons, nitrogens, and oxygens of the H-trisaccharide are colored yellow, blue, and red, respectively. Disulfide bridges are shown in orange. Green dotted lines represent hydrogen bonds; black dotted lines indicate hydrophobic effects. (C) View rotated 90° from (B) that highlights the continuous β sheet and the H-trisaccharide binding site on the concave surface. [View Larger Version of this Image (42K GIF file)]

Figure 2 Fig. 2.. The H-trisaccharide binding site of RBC36. (A) VLR residues involved in recognizing the H-trisaccharide. After refinement, a 2FobsFcalc electron density map was calculated and contoured at 2{sigma} as a blue mesh around the H-trisaccharide. Colors are as in Fig. 1. (B) H-trisaccharide interaction with RBC36 including solvent molecules, modified from the ligand interaction calculation by the program MOE (33). O in a circle represents waters. Hydrogen bonds with RBC36 residues and solvent molecules are drawn with green and pale green lines, respectively. Trp204, which is important for stabilizing the galactose via hydrophobic and stacking effects, is shown in a green circle beside the galactose sugar ring (14). (C) Sequence variability plot for amino acid residues from LRRNT to LRRCT of known VLRs. Green bars on the bottom represent residues on the concave surface; the red bar in the LRRCT shows the location of the highly variable insert. (D) Sequence alignment of LRR modules of RBC36 (14). The green bar shows the residues on the concave surface. Blue and red asterisks represent residues forming the β sheet and side chains that face the concave surface, respectively. Letters on yellow, blue, and red backgrounds show conserved hydrophobic residues, asparagine residues, and residues in the highly variable insert, respectively. Key residues on the concave surface (Asp103, Asp152, and Gln153) for the H-trisaccharide interaction are shown as red letters; Trp204 in the highly variable insert is indicated by a black asterisk at the left. (E) The conformation of the LRRVe module highlights the tight packing of the conserved hydrophobic residues, with their van der Waals radii outlined in dots. The seven residues that form the concave surface are numbered from the N terminus to the C terminus of the LRR. [View Larger Version of this Image (68K GIF file)]

Figure 3 Fig. 3.. Highly variable inserts of VLRs. (A) Crystal structures of lamprey RBC36 and three hagfish VLRs are superposed. C{alpha} trace for different VLRs: RBC36 in green, VLRA.29 in blue (PDB ID 2O6Q), VLRB.59 in orange (PDB ID 2O6S), and VLRB.61 in magenta (PDB ID 2O6R), respectively. Highly variable inserts are drawn in cartoon representation. (B) Superposition of RBC36–H-trisaccharide complex and GpIb{alpha}-VWF A1 domain complex (PDB ID 1M10). Overall RBC36-ECD structure is rotated 180° vertically from (A) to highlight the comparison of the highly variable insert of RBC36 and the β switch of GpIb{alpha}. RBC36 is depicted as a green trace, GpIb{alpha} as an orange trace, VWF A1 domain as a surface representation in cyan, and the H-trisaccharide as in Fig. 1. The β hairpin of the highly variable insert of RBC36 and the β switch of GpIb{alpha} are shown in cartoon representation. [View Larger Version of this Image (43K GIF file)]

Figure 4 Fig. 4.. The Interaction matrix of VLRs. (A) Seven residues on the concave surface of each LRR modules are shown as a main-chain stick model in the same view with Fig. 1C, and the C{alpha} atoms are connected by black lines. Five residues of the seven on the concave face (1, 2, 4, 6, and 7) are available for the antigen recognition and are connected laterally by black lines; the third and fifth residues face inward to the hydrophobic core and are connected by yellow lines. (B) The simplified interaction matrix of (A). Residues involved in hydrogen bonds or in van der Waals contacts are labeled in a circle or in a square, respectively. [View Larger Version of this Image (55K GIF file)]

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