MOLECULAR MODELING OF IMMUNOGLOBULIN LIGHT-CHAINS IMPLICATES HYDROPHOBIC RESIDUES IN NONAMYLOID LIGHT-CHAIN DEPOSITION DISEASE

Light chain deposition disease is a severe complication of certain imm unoproliferative disorders, due to the secretion of a monoclonal light chain which precipitates close to basement membranes of several tissu es, A kappa isotype restriction and an unusual frequency of a variable region subgroup (V kappa IV) suggest that precise structural features govern the propensity of pathogenic light chains to precipitate in ex tracellular spaces, We studied primary structures of light chains from six patients with light chain deposition disease in comparison with l ight chains from other pathological conditions, Sequence alignment rev ealed the presence of certain amino acids only in light chain depositi on disease, in particular non-polar replacing hydrophilic residues, To determine the role of these residues, structures of the variable doma in from four kappa chains belonging to V kappa I and V kappa IV subgro ups responsible for deposition disease were modeled using known immuno globulins as templates, The most evident structural features shared by all pathogenic light chains were hydrophobic residues exposed to the solvent in complementarity determining regions 1 or 3, In contrast to immunoglobulin light chain-related amyloidosis, where deposition of or ganized material might be due to electrostatic interactions between li ght chain dimers, hydrophobic interactions could enhance amorphous pre cipitation in non-amyloid light chain deposition disease.