VARIABLE DOMAIN-STRUCTURE OF KAPPA-IV HUMAN LIGHT-CHAIN LEN - HIGH HOMOLOGY TO THE MURINE LIGHT-CHAIN MCPC603

Antibody light chains of the kappa subgroup are the predominant light chain component in human immune responses and are used almost exclusiv ely in the antibody repertoire of mice. Human kappa light chains compr ise four subgroups. To date, all crystallographic studies of human kap pa light chains were carried out on proteins of the kappa I subgroup. The light chain produced by multiple myeloma patient Len, was of the k appa IV subgroup, it differed by only one residue from the germ-line g ene encoded protein. The variable domain fragment of the light chain w as crystallized from ammonium sulfate in space group C222(1). The crys tal structure was determined by molecular replacement and refined at 1 .95 Angstrom resolution to an R-factor of 0.15. Protein Len has six ad ditional residues in its CDR1 segment compared to the kappa I proteins previously characterized. The kappa IV variable domain, Len, differs in only 23 of 113 residues from murine kappa light chain McPC603. The RMS deviation upon superimposing their alpha-carbons was 0.69 Angstrom . The CDRI segment of the human and murine variable domains have the s ame length and conformation although their amino acid sequences differ in 5 out of 17 residues. Structural features were identified that cou ld account for the significantly higher stability of the human kappa I V protein relative to its murine counterpart. This human kappa IV ligh t chain structure is the closest human homolog to a murine light chain and can be expected to facilitate detailed structural comparisons nec essary for effective humanization of murine antibodies. (C) 1998 Publi shed by Elsevier Science Ltd. All rights reserved.