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 certain immunoproliferative disorders, due to the secretion of a monoclonal light chain which precipitates close to basement membranes of several tissues. A kappa isotype restriction and an unusual frequency of a variable region subgroup (VkappaIV) suggest that precise structural features govern the propensity of pathogenic light chains to precipitate in extracellular spaces. We studied primary structures of light chains from six patients with light chain deposition disease in comparison with light chains from other pathological conditions. Sequence alignment revealed the presence of certain amino acids only in light chain deposition disease, in particular non-polar replacing hydrophilic residues. To determine the role of these residues, structures of the variable domain from four kappa chains belonging to VkappaI and VkappaIV subgroups responsible for deposition disease were modeled using known immunoglobulins 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 organized material might be due to electrostatic interactions between light chain dimers, hydrophobic interactions could enhance amorphous precipitation in non-amyloid light chain deposition disease.
Déret
S
S
Laboratoire d'Immunologie et Immunopathologie, CNRS URA 1172, Poitiers, France.
Chomilier
J
J
Huang
D B
DB
Preud'homme
J L
JL
Stevens
F J
FJ
Aucouturier
P
P
D000595:Amino Acid Sequence; D016208:Databases, Factual; D006942:Hypergammaglobulinemia / Q000378:metabolism*; D007147:Immunoglobulin Light Chains / Q000737:chemistry*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013237:Stereoisomerism; D013499:Surface Properties
D007147:Immunoglobulin Light Chains