Structural Insights into VLR Fine Specificity for Blood Group Carbohydrates

• Type of Material: Article
• Authors: Bernard C. Collins, Scripps Research Institute; Robin J. Gunn, Scripps Research Institute; Tanya R. McKitrick, Harvard Medical School; Richard D. Cummings, Harvard Medical School; Max Cooper, Emory University; Brantley R. Herrin, Emory University; Ian A. Wilson, Scripps Research Institute
• Language: English
• Date: 2017-11-07
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 Elsevier Ltd
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.str.2017.09.003
• Title of Journal or Parent Work: Structure
• ISSN: 0969-2126
• Volume: 25
• Issue: 11
• Start Page: 1667
• End Page: +
• Grant/Funding Information: The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH, National Institute of General Medical Sciences (including P41GM103393 and P41GM103694) and the National Cancer Institute (U01CA199882).; Use of the APS was supported by the DOE, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. Use of the SSRL, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy (DOE) Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515.; This work is supported by NIH grants R01 AI042266 (I.A.W.) and RO1 AI072435 (M.D.C.).; The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.
• Keywords: Life Sciences & Biomedicine; PROTEIN DESIGN; Cell Biology; VARIABLE LYMPHOCYTE RECEPTORS; Biochemistry & Molecular Biology; LAMPREY; BINDING; Biophysics; RECOGNITION; ULEX-EUROPAEUS; ANTIGEN; IMMUNE-RESPONSE; LECTIN-I; Science & Technology; MONOCLONAL-ANTIBODIES
• Research Categories: Biology, Molecular; Chemistry, Biochemistry

Abstract

High-quality reagents to study and detect glycans with high specificity for research and clinical applications are severely lacking. Here, we structurally and functionally characterize several variable lymphocyte receptor (VLR)-based antibodies from lampreys immunized with O erythrocytes that specifically recognize the blood group H-trisaccharide type II antigen. Glycan microarray analysis and biophysical data reveal that these VLRs exhibit greater specificity for H-trisaccharide compared with the plant lectin UEA-1, which is widely used in blood typing. Among these antibodies, O13 exhibits superior specificity for H-trisaccharide, the basis for which is revealed by comparative analysis of high-resolution VLR:glycan crystal structures. Using a structure-guided approach, we designed an O13 mutant with further enhanced specificity for H-trisaccharide. These insights into glycan recognition by VLRs suggest that lampreys can produce highly specific glycan antibodies, and are a valuable resource for the production of next-generation glycan reagents for biological and biomedical research and as diagnostics and therapeutics. Collins et al. identify and characterize glycan-specific VLR antibodies from immunized lamprey. Glycan array, biophysical, and structural analyses show their highly specific glycan binding properties. A VLR with superior specificity for the major O blood group antigen, H-trisaccharide, is identified by coupling the unconventional adaptive immune system of lamprey with structure-guided design.