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.