Differential Epitope Positioning within the Germline Antibody Paratope Enhances Promiscuity in the Primary Immune Response

Dhruv K. Sethi, Anupriya Agarwal, Venkatasamy Manivel, Kanury V.S. Rao, Dinakar M. Salunke

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Correlation between the promiscuity of the primary antibody response and conformational flexibility in a germline antibody was addressed by using germline antibody 36-65. Crystallographic analyses of the 36-65 Fab with three independent dodecapeptides provided mechanistic insights into the generation of antibody diversity. While four antigen-free Fab molecules provided a quantitative description of the conformational repertoire of the antibody CDRs, three Fab molecules bound to structurally diverse peptide epitopes exhibited a common paratope conformation. Each peptide revealed spatially different footprints within the antigen-combining site. However, a conformation-specific lock involving two shared residues, which were also associated with hapten binding, was discernible. Unlike the hapten, the peptides interacted with residues that undergo somatic mutations, suggesting a possible mechanism for excluding "nonspecific" antigens during affinity maturation. The observed multiple binding modes of diverse epitopes within a common paratope conformation of a germline antibody reveal a simple, yet elegant, mechanism for expanding the primary antibody repertoire.

Original languageEnglish (US)
Pages (from-to)429-438
Number of pages10
JournalImmunity
Volume24
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • MOLIMMUNO

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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