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Structural basis of the cross-reaction between an antibody to the Trypanosoma cruzi ribosomal P2ß protein and the human ß₁ adrenergic receptor

C. Smulski^*, V. Labovsky^*, G. Levy^*, M. Hontebeyrie, J. Hoebeke and M. J. Levin^*,,1

^* Laboratorio de Biología Molecular de la Enfermedad de Chagas (LaBMECh), Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI), National Research Council (CONICET), Buenos Aires, Argentina; Institut Pasteur, Paris, France;

UPR 9021 "Immunologie et Chimie Thérapeutiques" du C.N.R.S., Institut de Biologie Moleculaire et Cellulaire (IBMC), Strasbourg, France; and

Institut Cochin, Département Maladies Infectieuses, INSERM U567, Paris, France

¹Correspondence: LaBMECh, Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (INGEBI-CONICET), Vta. de Obligado 2490, C1428ADN, Ciudad de Buenos Aires, Argentina. E-mail: mlevin{at}dna.uba.ar

Antibodies from patients with Chagas heart disease and monoclonal antibodies (or mAb) to the carboxy-terminal end (B cell epitope R13) of the ribosomal P2ß protein of Trypanosoma cruzi (TcP2ß) cross-react with the ß₁ adrenergic receptor (ß₁-AR). Two single-chain Fv fragments (scFv) C5 and B7 derived from the variable regions of the anti-R13 mAb 17.2 were expressed. scFv C5 was a dimer and bound to TcP2ß with an affinity of K_d = 8 nM, whereas scFv B7 was monomeric and had less affinity than scFv C5 for TcP2ß, K_d = 46 nM. The affinity constant of scFv C5 to the second extracellular loop of the human ß₁-AR was of 10 µM. Moreover, scFv C5 induced an increase in cAMP levels of CHO-K cells transfected with the human ß₁-AR; scFv B7 had no effect but blocked isoproterenol stimulation. The agonist-like activity of scFv C5 and the antagonist activity of scFv B7 were both confirmed in vivo on heart beating frequency after their passive transfer to mice. Molecular modeling of the variable region of mAb 17.2 indicated which amino acids were likely to be involved in recognizing both peptide EDDDMGFGLF, derived from the R13 epitope of TcP2ß, and peptide ESDEARRCYN from the second extracellular loop of the human ß₁-AR. It is plausible that the recently described cross-reaction of mAb 17.2 with rhodopsin can also be explained by this model. The physiological effects of this type of anti-T. cruzi antibodies may increase the liability of patients with Chagas disease.—Smulski, C., Labovsky, V., Levy, G., Hontebeyrie, M., Hoebeke, J., Levin, M. J. Structural basis of the cross-reaction between an antibody to the Trypanosoma cruzi ribosomal P2ß protein and the human ß₁ adrenergic receptor.

Key Words: ribosomal P proteins • single-chain Fv fragments (scFv) • paratope-epitope modeling