Cell Biology

Ultralong Antibodies

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Science  21 Jun 2013:
Vol. 340, Issue 6139, pp. 1377
DOI: 10.1126/science.340.6139.1377-c

An antibody's specificity for antigens is largely determined by complementarity-determining regions (CDRs). These form protein loops of the heavy and light chains that bind to a target. The most diverse is region 3 of the immunoglobulin heavy chain (CDR H3), which forms a flat binding surface for antigens. However, 10% of all bovine antibodies bear a much longer loop that includes many cysteines. Wang et al. analyzed the crystal structures of two such cow antibodies and discovered that the stretch of residues forms a long stalk that protrudes from the antibody and terminates in a knob domain. The two antibodies have different disulfide bond patterns in the knob, which arise from different cysteine sequence positions. The stalks also differ in length, which alters the relative position of the knob domain. Sequencing of more than 10,000 ultralong CDR H3s indicates that the diversity (D) gene segment appears primed for mutation to cysteine, allowing new disulfide bonds to be made or broken. The authors propose that the cow's immune system uses cysteine diversification to increase the repertoire of unique “minifolds” in knob domains, thereby expanding the antibody arsenal for recognizing foreign targets.

Cell 153, 10.1016/j.cell.2013.04.049 (2013).

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