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Functional consequences of insertions and deletions in the complementarity-determining regions of human antibodies

Lantto, Johan LU and Ohlin, Mats LU (2002) In Journal of Biological Chemistry 277(47). p.45108-45114
Abstract
Insertions and deletions of nucleotides in the genes encoding the variable domains of antibodies are natural components of the hypermutation process, which may expand the available repertoire of hypervariable loop lengths and conformations. Although insertion of amino acids has also been utilized in antibody engineering, little is known about the functional consequences of such modifications. To investigate this further, we have introduced single-codon insertions and deletions as well as more complex modifications in the complementarity-determining regions of human antibody fragments with different specificities. Our results demonstrate that single amino acid insertions and deletions are generally well tolerated and permit production of... (More)
Insertions and deletions of nucleotides in the genes encoding the variable domains of antibodies are natural components of the hypermutation process, which may expand the available repertoire of hypervariable loop lengths and conformations. Although insertion of amino acids has also been utilized in antibody engineering, little is known about the functional consequences of such modifications. To investigate this further, we have introduced single-codon insertions and deletions as well as more complex modifications in the complementarity-determining regions of human antibody fragments with different specificities. Our results demonstrate that single amino acid insertions and deletions are generally well tolerated and permit production of stably folded proteins, often with retained antigen recognition, despite the fact that the thus modified loops carry amino acids that are disallowed at key residue positions in canonical loops of the corresponding length or are of a length not associated with a known canonical structure. We have thus shown that single-codon insertions and deletions can efficiently be utilized to expand structure and sequence space of the antigen-binding site beyond what is encoded by the germline gene repertoire. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
277
issue
47
pages
45108 - 45114
publisher
ASBMB
external identifiers
  • wos:000179404800067
  • scopus:0037160031
ISSN
1083-351X
DOI
10.1074/jbc.M208401200
language
English
LU publication?
yes
id
fdee3e00-4bd0-4d2c-9086-dc2f3318f703 (old id 322822)
date added to LUP
2007-11-07 16:00:46
date last changed
2017-01-01 05:10:39
@article{fdee3e00-4bd0-4d2c-9086-dc2f3318f703,
  abstract     = {Insertions and deletions of nucleotides in the genes encoding the variable domains of antibodies are natural components of the hypermutation process, which may expand the available repertoire of hypervariable loop lengths and conformations. Although insertion of amino acids has also been utilized in antibody engineering, little is known about the functional consequences of such modifications. To investigate this further, we have introduced single-codon insertions and deletions as well as more complex modifications in the complementarity-determining regions of human antibody fragments with different specificities. Our results demonstrate that single amino acid insertions and deletions are generally well tolerated and permit production of stably folded proteins, often with retained antigen recognition, despite the fact that the thus modified loops carry amino acids that are disallowed at key residue positions in canonical loops of the corresponding length or are of a length not associated with a known canonical structure. We have thus shown that single-codon insertions and deletions can efficiently be utilized to expand structure and sequence space of the antigen-binding site beyond what is encoded by the germline gene repertoire.},
  author       = {Lantto, Johan and Ohlin, Mats},
  issn         = {1083-351X},
  language     = {eng},
  number       = {47},
  pages        = {45108--45114},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Functional consequences of insertions and deletions in the complementarity-determining regions of human antibodies},
  url          = {http://dx.doi.org/10.1074/jbc.M208401200},
  volume       = {277},
  year         = {2002},
}