TY - JOUR
T1 - Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures
AU - Zemlin, Michael
AU - Klinger, Martin
AU - Link, Jason
AU - Zemlin, Cosima
AU - Bauer, Karl
AU - Engler, Jeffrey A.
AU - Schroeder, Harry W.
AU - Kirkham, Perry M.
N1 - Funding Information:
The authors thank Andrew C. Martin (Great Britain) for help using the KabatMan web site, and Alberto Nobrega (Brazil) & Roberto Sitia (Italy) for helpful discussions. This work was supported, in part, by Alexander von Humboldt-Foundation grant FLF1071857 (to M.Z.), the Dystonia Medical Research Foundation (to P.M.K.), Deutsche Forschungsgemeinschaft BA1187/6-1 (to K.B. and M.Z.), a grant from the UAB Health services foundation (to J.A.E.), and National Institutes of Health AI42732 and AI48115 (to H.W.S. Jr).
PY - 2003/12/5
Y1 - 2003/12/5
N2 - Immunoglobulin junctional diversity is concentrated in the third complementarity-determining region of the heavy chain (CDR-H3), which often plays a dominant role in antigen binding. The range of CDR-H3 lengths in mouse is shorter than in human, and thus the murine repertoire could be presumed to be a subset of the human one. To test this presumption, we analyzed 4751 human and 2170 murine unique, functional, published CDR-H3 intervals. Although tyrosine, glycine, and serine were found to predominate in both species, the human sequences contained fewer tyrosine residues, more proline residues, and more hydrophobic residues (p<0.001, respectively). While changes in amino acid utilization as a function of CDR-H3 length followed similar trends in both species, murine and human CDR-H3 intervals of identical length were found to differ from each other. These differences reflect both divergence of germline diversity and joining gene sequence and somatic selection. Together, these factors promote the production of a rather uniform repertoire in mice of tyrosine-enriched CDR-H3 loops with stabilized hydrogen bond-ladders versus a much more diverse repertoire in human that contains CDR-H3 loops sculpted by the presence of intra-chain disulfide bonds due to germline-encoded cysteine residues as well as the enhanced presence of somatically generated proline residues that preclude hydrogen bond ladder formation. Thus, despite the presumed need to recognize a similar range of antigen epitopes, the murine CDR-H3 repertoire is clearly distinct from its human counterpart in its amino acid composition and its predicted range of structures. These findings represent a benchmark to which CDR-H3 repertoires can be compared to better characterize and understand the shaping of the CDR-H3 repertoire over evolution and during immune responses. This information may also be useful for the design of species-specific CDR-H3 sequences in synthetic antibody libraries.
AB - Immunoglobulin junctional diversity is concentrated in the third complementarity-determining region of the heavy chain (CDR-H3), which often plays a dominant role in antigen binding. The range of CDR-H3 lengths in mouse is shorter than in human, and thus the murine repertoire could be presumed to be a subset of the human one. To test this presumption, we analyzed 4751 human and 2170 murine unique, functional, published CDR-H3 intervals. Although tyrosine, glycine, and serine were found to predominate in both species, the human sequences contained fewer tyrosine residues, more proline residues, and more hydrophobic residues (p<0.001, respectively). While changes in amino acid utilization as a function of CDR-H3 length followed similar trends in both species, murine and human CDR-H3 intervals of identical length were found to differ from each other. These differences reflect both divergence of germline diversity and joining gene sequence and somatic selection. Together, these factors promote the production of a rather uniform repertoire in mice of tyrosine-enriched CDR-H3 loops with stabilized hydrogen bond-ladders versus a much more diverse repertoire in human that contains CDR-H3 loops sculpted by the presence of intra-chain disulfide bonds due to germline-encoded cysteine residues as well as the enhanced presence of somatically generated proline residues that preclude hydrogen bond ladder formation. Thus, despite the presumed need to recognize a similar range of antigen epitopes, the murine CDR-H3 repertoire is clearly distinct from its human counterpart in its amino acid composition and its predicted range of structures. These findings represent a benchmark to which CDR-H3 repertoires can be compared to better characterize and understand the shaping of the CDR-H3 repertoire over evolution and during immune responses. This information may also be useful for the design of species-specific CDR-H3 sequences in synthetic antibody libraries.
KW - Amino acid composition
KW - Antibody engineering
KW - Immunoglobulin heavy chain complementarity-determining region 3
KW - Intra-chain disulfide bonds
KW - Predicted structure
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U2 - 10.1016/j.jmb.2003.10.007
DO - 10.1016/j.jmb.2003.10.007
M3 - Article
C2 - 14636599
AN - SCOPUS:0242551578
SN - 0022-2836
VL - 334
SP - 733
EP - 749
JO - Journal of molecular biology
JF - Journal of molecular biology
IS - 4
ER -