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Germline Antibodies Paratope Interactions In Adjustable Locks and Flexible Keys: Plasticity of Epitope−Paratope Interactions in Germline Antibodies This information is current as Tarique Khan and Dinakar M. Salunke of October 2, 2021. J Immunol 2014; 192:5398-5405; Prepublished online 30 April 2014; doi: 10.4049/jimmunol.1302143 http://www.jimmunol.org/content/192/11/5398 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/04/30/jimmunol.130214 Material 3.DCSupplemental References This article cites 41 articles, 14 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/192/11/5398.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 2, 2021 • Fast Publication! 4 weeks from acceptance to publication *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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Adjustable Locks and Flexible Keys: Plasticity of Epitope–Paratope Interactions in Germline Antibodies Tarique Khan*,1 and Dinakar M. Salunke*,† Ag recognition by independent primary Abs against a small flexible Ag with overlapping epitopes was analyzed to address the deter- minants of Ag specificity during the initial encounter. Crystal structures of two distinct dodecapeptide Ags, GDPRPSYISHLL and PPYPAWHAPGNI, in complex with the germline mAb 36-65 were determined and compared with the structures of the same Ags bound to another independent germline mAb, BBE6.12H3. For each peptide Ag, the two germline mAbs recognized overlapping epitopes, but in different topologies. The peptide structures differed, and the two paratopes attained discrete conformations, leading to different surface topologies, in a mode that can be described as adjustable locks and flexible keys. This is in contrast to mature mAbs, in which confor- mational convergence of different paratopes while binding to a common epitope in a similar conformation has been reported. These results suggest that the primary immune receptor repertoire is highly versatile as compared with its mature counterpart. Germline and mature mAbs adopt distinct mechanisms for recognizing a flexible epitope. Whereas conservation of conformational repertoire Downloaded from is a key characteristic of mature mAbs achieved through affinity maturation, the germline mAbs, at the initial stages of Ag encounter, maintain substantial plasticity, accommodating a broad specificity repertoire. The Journal of Immunology, 2014, 192: 5398–5405. he clonal selection theory (1) predicts a correlation between recognition. Previous structural studies have provided insights on how antigenic determinants and the corresponding Abs, implying germline Ab pluripotency may enhance the BCR repertoire diversity T that each B lymphocyte expresses a unique BCR (Ab) that (4, 5, 8–10). Comparative analysis of degeneracy in interactions of http://www.jimmunol.org/ can respond to an incoming binding Ag without having been previ- germline versus affinity-matured Abs with antigenic targets would ously exposed to it. Degenerate reactivity of individual germline Abs contribute further to the understanding of the structural mechanisms has been suggested to be a physiological requirement in response to operating in the configuration of B cell immune responses. the potentially infinite antigenic repertoire to be encountered by the In the current study, we have addressed the versatility of Ag humoral immune system (2–5), although immune evasion by patho- recognition at the initial encounter by analyzing the binding of Ags gens through escape mutations provides evidence for the limitations of with overlapping epitopes by genetically independent germline the germline repertoire. In any case, the population of B cells avail- Abs. The crystal structures of mAb 36-65 in complex with the able at any point does not present the entire potential repertoire. peptide epitopes GDPRPSYISHLL (Gdp) and PPYPAWHAPGNI Therefore, to be able to respond each time exposure occurs, the hu- (Ppy) (2) were investigated by x-ray crystallography. These by guest on October 2, 2021 moral immune system has to be able to use its resources economi- structures were compared with complexes of the same peptides cally, including being able to use the same BCR to recognize different with another independent mAb BBE6.12H3 to understand the Ags as well as to use different BCRs to recognize the same Ag. structural bases of their recognition. The H chain V region of mAb Naive germline BCRs are likely to need rapid identification and 36-65 has been shown to be constructed from VH J558, DH selection upon exposure to initiate an immune response. In contrast, Fl16.1, and JH2 gene segments, whereas mAb BBE6.12H3 con- affinity-matured Abs develop through selection by prolonged exposure sists of VH 186.2, DH Fl16.1, and JH2 (11–13). Furthermore, to the dominant conformation of the Ag. It is only after the selection of mAbs 36-65 and BBE6.12H3 use L chains of the k and l isotypes, high-affinity B cells in germinal centers that affinity maturation and respectively (12, 13). L chain CDRs adopt distinct canonical clonal expansion follow (6, 7). Therefore, it is interesting to address conformations as defined by Chothia et al. (14). Thus, mAbs 36-65 the structural mechanisms adopted by germline encoded BCRs for Ag and BBE6.12H3 represent Abs of independent origin having dis- tinct CDR sequences (Fig. 1). Their structures and binding prop- *National Institute of Immunology, New Delhi 110067, India; and †Regional Centre erties have already been extensively investigated (2, 4, 5). for Biotechnology, Gurgaon 122016, India We have previously explored mechanistic details of mAb 1Current address: Department of Biochemistry, University of Texas Southwestern BBE6.12H3 binding to these peptides (4). Further analyses of the Medical Center, Dallas, TX. same peptides bound to the germline mAb 36-65 have allowed us to Received for publication August 16, 2013. Accepted for publication March 27, 2014. compare the recognition of a flexible Ag by independent germline This work was supported by the Department of Biotechnology, Government of India. Abs. Comparative analyses of these structures show that entirely The coordinates and structure factors presented in this article have been submitted to different CDR sequences are involved in the interaction with the the Research Collaboratory for Structural Bioinformatics Protein Data Bank (http:// www.pdb.org) under accession codes 4bh7 and 4bh8. peptide Ags. These data provide structural understanding of the ways in which specific recognition of a given Ag can be achieved by Address correspondence and reprint requests to Dr. Dinakar M. Salunke, Regional Centre for Biotechnology, 180, Udyog Vihar Phase-I, Gurgaon, Haryana 122016, many different VDJ/VJ combinations in the remarkably adaptable India. E-mail address: [email protected] naive immune receptor repertoire. Our studies also reveal how un- The online version of this article contains supplemental material. related Abs structurally adjust to recognize a flexible Ag and indicate Abbreviations used in this article: CNS, Crystallography and NMR System; Gdp, that the primary B cell response is likely composed of BCRs having GDPRPSYISHLL; PDB, Protein Data Bank; PEG, polyethylene glycol; Ppy, PPY- a high degree of structural adaptability. In contrast, our comparison PAWHAPGNI; RMSD, root mean square deviation. of flexible Ag recognition by germline versus affinity-matured Abs Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 shows that they adopt distinct structural mechanisms. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1302143 The Journal of Immunology 5399 Materials and Methods Refinement and model building Peptides The Crystallography andNMRSystem(CNS)suitewasusedforstructure The dodecameric peptides used in this study were identified in a previous refinement (19). Both Rwork (Crystallographic R-factor) and Rfree (Free R- study by using a phage display peptide library kit (New England Biolabs, factor) (19) values were monitored during the refinement. We used 10% of the Cambridge, MA) (2). Briefly, the germline mAb BBE6.12H3 was shown total reflections in each case for calculation of Rfree values. Rigid body re- to bind to a series of independent peptides from a random phage display finement was carried out for the complete F(ab) molecule, and VH,VL,CH, library. From this set, two independent clones, 3 (GDPRPSYISHLL) and and CL domains were treated as discrete units. The models were further re- BA7-09 (PPYPAWHAPGNI), which hereafter would be referred to as Gdp fined by using positional and temperature factor refinement protocols of CNS. and Ppy, were selected for crystallographic analyses with the mAb 36-65 in COOT was used for model building and to display electron-density maps (20). the current study. These peptides were synthesized by the solid-phase method Final structures
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