Molecular modeling of immunoglobulin light chains implicates hydrophobic residues in non-amyloid light chain deposition disease

Light chain deposition disease is a severe complication of certainimmunoproliferative disorders, due to the secretion of a monoclonal lightchain which precipitates close to basement membranes of several tissues. Akappa isotype restriction and an unusual frequency of a variable regionsubgroup (VkappaIV) suggest that precise structural features govern thepropensity of pathogenic light chains to precipitate in extracellularspaces. We studied primary structures of light chains from six patientswith light chain deposition disease in comparison with light chains fromother pathological conditions. Sequence alignment revealed the presence ofcertain amino acids only in light chain deposition disease, in particularnon-polar replacing hydrophilic residues. To determine the role of theseresidues, structures of the variable domain from four kappa chainsbelonging to VkappaI and VkappaIV subgroups responsible for depositiondisease were modeled using known immunoglobulins as templates. The mostevident structural features shared by all pathogenic light chains werehydrophobic residues exposed to the solvent in complementarity determiningregions 1 or 3. In contrast to immunoglobulin light chain- relatedamyloidosis, where deposition of organized material might be due toelectrostatic interactions between light chain dimers, hydrophobicinteractions could enhance amorphous precipitation in non- amyloid lightchain deposition disease.