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Very few substitutions in a germ line antibody are required to initiate significant domain exchange

Academic Article
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Overview

authors

  • Huber, M.
  • Le, K. M.
  • Doores, K. J.
  • Fulton, Z.
  • Stanfield, Robyn
  • Wilson, Ian
  • Burton, Dennis

publication date

  • October 2010

journal

  • Journal of Virology  Journal

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.

subject areas

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV-1
  • Humans
  • Immunoglobulin Variable Region
  • Models, Molecular
  • Molecular Sequence Data
  • Polysaccharides
  • Protein Structure, Tertiary
  • Sequence Homology, Amino Acid
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Identity

PubMed Central ID

  • PMC2950590

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.01111-10

PubMed ID

  • 20702640
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Additional Document Info

start page

  • 10700

end page

  • 10707

volume

  • 84

issue

  • 20

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