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A Human Igm Cold Agglutinin Three-Dimensional Structure of The Three-Dimensional Structure of the Fab from a Human IgM Cold Agglutinin Ana Cauerhff, Bradford C. Braden, Julio Garcia Carvalho, Ricardo Aparicio, Igor Polikarpov, Juliana Leoni and This information is current as Fernando A. Goldbaum of September 24, 2021. J Immunol 2000; 165:6422-6428; ; doi: 10.4049/jimmunol.165.11.6422 http://www.jimmunol.org/content/165/11/6422 Downloaded from References This article cites 57 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/165/11/6422.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2000 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Three-Dimensional Structure of the Fab from a Human IgM Cold Agglutinin1 Ana Cauerhff,* Bradford C. Braden,† Julio Garcia Carvalho,‡ Ricardo Aparicio,‡ Igor Polikarpov,‡ Juliana Leoni,* and Fernando A. Goldbaum2§ Cold agglutinins (CAs) are IgM autoantibodies characterized by their ability to agglutinate in vitro RBC at low temperatures. These autoantibodies cause hemolytic anemia in patients with CA disease. Many diverse Ags are recognized by CAs, most frequently those belonging to the I/i system. These are oligosaccharides composed of repeated units of N-acetyllactosamine, expressed on RBC. The three-dimensional structure of the Fab of KAU, a human monoclonal IgM CA with anti-I activity, was determined. The KAU combining site shows an extended cavity and a neighboring pocket. Residues from the hypervariable loops VHCDR3, VLCDR1, and VLCDR3 form the cavity, whereas the small pocket is defined essentially by residues from the hyper- Downloaded from variable loops VHCDR1 and VHCDR2. This fact could explain the VH4-34 germline gene restriction among CA. The KAU combining site topography is consistent with one that binds a polysaccharide. The combining site overall dimensions are 15 Å wide and 24 Å long. Conservation of key binding site residues among anti-I/i CAs indicates that this is a common feature of this family of autoantibodies. We also describe the first high resolution structure of the human IgM CH1:CL domain. The structural analysis shows that the CH1-CL interface is mainly conserved during the isotype switch process from IgM to IgG1. The Journal of Immunology, 2000, 165: 6422–6428. http://www.jimmunol.org/ old agglutinins (CAs)3 are IgM autoantibodies character- isolated CA molecule. This phenomenon is called “idiotypic cross- ized by their ability to agglutinate in vitro RBC at low specificity” because these types of autoantibodies share an anti- C temperatures (4–22°C) (1, 2). These autoantibodies genic structure (or idiotope). The rat mAb 9G4 (11) served to cause hemolytic anemia in patients with CA disease (CAD). CAs identify the cross-reacting idiotope associated with the expression appear in the context of monoclonal gammopathies secondary to B of a particular variable domain of the heavy chain (VH) region. cell dyscrasias ranging from benign to malignant lymphoprolifera- Amino acid and nucleotide sequence analyses have confirmed this tion (3–5). They can also be detected in normal patients at low VH as derived from the VH4-34 (VH4-21) germline gene (12, 13). titers (6), though these titers increase with different infectious pro- The presence of a V chain derived from V 4-34 is necessary both H H by guest on September 24, 2021 cesses (7–9). for the CA property and for the idiotope that is recognized by 9G4 Many diverse Ags are recognized by CAs, most frequently those mAb. Abs derived from the VH4-34 gene also recognize different belonging to the I/i system. These are oligosaccharides composed autoantigens as is the case of some rheumatoid factors (14), anti- of repeated units of N-acetyllactosamine, expressed in a linear DNA Abs (15), and the anti-D Abs (16). form (i) on fetal RBC or in a branched form (I) on adult RBC. Anti-I/i CAs show a great variability in VHCDR3, suggesting Early studies revealed that the vast majority of Abs with CA that this hypervariable region could not be directly involved in the activity reacted with a polyclonal antiserum (10) generated by an specific recognition or that the mode of binding is different among CAs. Li et al. (17) postulated that the VHFR1 region is essential *Ca´tedra de Inmunologı´a, Instituto de Estudios de la Inmunidad Humoral (IDEHU), in the specific recognition of the anti-I/i system, whereas the Facultad de Farmacia y Bioquı´mica UBA, Buenos Aires, Argentina; †Department of VHCDR3 and variable domain of the light chain (VL) dictate the Natural Sciences, Bowie State University, Bowie, MD 20715; ‡Laborato´rio Nacional de Luz Sı´ncrotron, Campinas, Brazil; and §Instituto de Investigaciones Bioquı´micas fine specificity and strength of binding. Most of the anti-I CAs VL (Fundacio´n Campomar, IIBBA-CONICET, FCEN-UBA), Buenos Aires, Argentina domains are derived from the V␬III germline gene, although some Received for publication March 2, 2000. Accepted for publication September 7, 2000. are encoded by V␬IorV␬II. In contrast, CAs with anti-i activity The costs of publication of this article were defrayed in part by the payment of page make no preferential usage of L chains. charges. This article must therefore be hereby marked advertisement in accordance The IgM KAU CA was obtained from the serum of a patient with 18 U.S.C. Section 1734 solely to indicate this fact. suffering CAD. Its amino acid sequence has been determined by 1 This work was supported by grants and fellowships from the Consejo Nacional de Investigaciones Cientı´ficas y Te´cnicas (CONICET), Fundacio´n Antorchas, and the Leoni and coworkers (18). As all CAs that recognize the I/i sys- University of Buenos Aires (to A.C., J.L., and F.A.G.). B.C.B. was supported by tem, the VH domain is derived from the VH4-34 germline gene, National Institutes of Health Grant 1R15AI44790-01 and National Aeronautics and showing a single point mutation in the VHCDR1 (Gly31Asp). The Space Administration Grant NCC5-232 (Model Institutes for Excellence). J.G.C., ␬ R.A., and I.P. were supported by Fundac¸ao de Amparo a`Pesquisa do Estado de Sao VL domain is derived from the kv305 germline gene (V IIIb). The Paulo (via Grant 1996/2285-5) and Conselho Nacional de Pesquisas (Brazil). Fab from IgM KAU was crystallized, and preliminary x-ray dif- 2 Address correspondence and reprint requests to Dr. Fernando Goldbaum, Instituto fraction data was reported (19). de Investigaciones Bioquı´micas, Fundacio´n Campomar, Av. Patricias Argentinas 435, Here we present the three-dimensional structure of the Fab Buenos Aires 1405, Argentina. E-mail address: [email protected] KAU. Its combining site shows an extended cavity, as expected of 3 Abbreviations used in this paper: CA, cold agglutinin; CAD, CA disease; V , vari- H an anti-carbohydrate Ab. Conservation of key binding site residues able domain of the heavy chain; VL, variable domain of the light chain; CDR, comple- mentarity-determining region; FR, framework region; CH1, first constant domain of among anti-I/i CAs indicates that this is a common feature of this the heavy chain; CL, constant domain of the light chain; C␮1, first constant domain of the IgM ␮ heavy chain; anti-Id, anti-idiotypic Ab; rmsd, root mean square deviation; family of autoantibodies. We also describe the first high-resolution PDB, Protein Data Bank. structure of the human IgM first constant domain of the heavy Copyright © 2000 by The American Association of Immunologists 0022-1767/00/$02.00 The Journal of Immunology 6423 chain:constant domain of the light chain (CH1:CL) domain and and 199–201 have no associated electron density and have been removed compare its features with those of other human and murine from the model. Likewise, CH1 residues 135–142 and 199–201 in the isotypes. second Fab have been removed due to lack of electron density. All residues in the VL,CL, and VH domains of both molecules are well resolved. Only two nonglycyl residues in each Fab, VL Ala52 and VH Asp31, are in dis- Materials and Methods allowed regions of a Ramachandran plot (data not shown). Similar occur- Molecular replacement and structure refinement rences in tight turns have been observed in other Fabs (27–29). Calculation of a Fo-Fc difference Fourier map using the final model In a previous work (19) we described the preliminary x-ray diffraction of coordinates reveals electron densities at the CH1 glycosylation site. This a single crystal of Fab KAU to a resolution of 2.8 Å. Using synchrotron density is continuous with the side chain of CH1 Asn166, indicating co- light at the Laboratorio Nacional de Luz Sincrotron (LNLS, Campinas, valent bonding to the Fab. However, this density is unresolved, with breaks Brazil) we obtained a data set comprising 31,333 unique reflections (96.8% in the glycosidic linkages, and is only approximately the length of a tri- complete between 13.0 and 2.8 Å resolution, 99.0% complete in the last saccharide.
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