Structural analysis of the amyloidogenic kappa Bence Jones protein (FUR)

Patients with systemic amyloidosis associated with multiple myeloma (AL-amy loidosis) exhibit immunoglobulin light chains and fragments which have been identified as amyloid protein. Since a relatively small proportion of pati ents with multiple myeloma develop AL-amyloidosis, comparison of the amino acid sequence of the amyloidogenic and non-amyloidogenic immunoglobulin lig ht chains and the structural characterization of the amyloid proteins are r equired to understand the relationship between structure and amyloidogenici ty. We determined the primary structure of a kappa I-type Bence Jones prote in obtained from a patient (FUR) who had systemic AL-amyloidosis associated with multiple myeloma. We identified eight amino acid replacements unique to this patient among the amyloidogenic kappa I-light chains, and which are also rare among the known kappa type light chains of humans. Three of thes e substitutions were within the framework regions and may act to destabiliz e the structure to promote a putative amyloidogenic conformation. In contra st to light chain fragments in the urine, which were processed in the varia ble region, mass spectrometric analysis of the fibril proteins isolated fro m lingual amyloid deposits in this patient, revealed that they were all tru ncated within the constant region and corresponded to residues 1-125, 1-144 and 1-210. Inspection of the predicted three-dimensional model of this pro tein suggested that these fragments may be generated by a protease specific for the N-terminal sides of basic amino acids. These findings suggest that amino acid substitutions at highly conserved residues may convert non-amyl oidogenic to amyloidogenic immunoglobulin light chain proteins.