PMID: 20702640
Title: Very few substitutions in a germ line antibody are required to initiate significant domain exchange
Abstract: 2G12 is a broadly neutralizing anti-HIV-1 monoclonal human IgG1 antibody reactive with a high-mannose glycan cluster on the surface of glycoprotein gp120. A key feature of this very highly mutated antibody is domain exchange of the heavy-chain variable region (V(H)) with the V(H) of the adjacent Fab of the same immunoglobulin, which assembles a multivalent binding interface composed of two primary binding sites in close proximity. A non-germ line-encoded proline in the elbow between V(H) and C(H)1 and an extensive network of hydrophobic interactions in the V(H)/V(H)' interface have been proposed to be crucial for domain exchange. To investigate the origins of domain exchange, a germ line version of 2G12 that behaves as a conventional antibody was engineered. Substitution of 5 to 7 residues for those of the wild type produced a significant fraction of domain-exchanged molecules, with no evidence of equilibrium between domain-exchanged and conventional forms. Two substitutions not previously implicated, A(H14) and E(H75), are the most crucial for domain exchange, together with I(H19) at the V(H)/V(H)' interface and P(H113) in the elbow region. Structural modeling gave clues as to why these residues are essential for domain exchange. The demonstration that domain exchange can be initiated by a small number of substitutions in a germ line antibody suggests that the evolution of a domain-exchanged antibody response in vivo may be more readily achieved than considered to date.
Date: 1970-08-21
Year: 2011
Journal: J. Virol.
PMID Author: Huber M, Le KM, Doores KJ, Fulton Z, Stanfield RL, Wilson IA, Burton DR
PMC Link #: PMC2950590

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