Light chain, or AL, amyloidosis is a pathological condition arising from 
systemic extracellular deposition of monoclonal immunoglobulin light chain 
variable domains in the form of insoluble amyloid fibrils, especially in the 
kidneys. Substantial evidence suggests that amyloid fibril formation from native 
proteins occurs via a conformational change leading to a partially folded 
intermediate conformation, whose subsequent association is a key step in 
fibrillation. In the present investigation, we have examined the properties of a 
recombinant amyloidogenic light chain variable domain, SMA, to determine whether 
partially folded intermediates can be detected and correlated with aggregation. 
The results from spectroscopic and hydrodynamic measurements, including far- and 
near-UV circular dichroism, FTIR, NMR, and intrinsic tryptophan fluorescence and 
small-angle X-ray scattering, reveal the build-up of two partially folded 
intermediate conformational states as the pH is decreased (low pH destabilized 
the protein and accelerated the kinetics of aggregation). A relatively 
nativelike intermediate, I(N), was observed between pH 4 and 6, with little loss 
of secondary structure, but with significant tertiary structure changes and 
enhanced ANS binding, indicating exposed hydrophobic surfaces. At pH below 3, we 
observed a relatively unfolded, but compact, intermediate, I(U), which was 
characterized by decreased tertiary and secondary structure. The I(U) 
intermediate readily forms amyloid fibrils, whereas I(N) preferentially leads to 
amorphous aggregates. Except at pH 2, where negligible amorphous aggregate is 
formed, the amorphous aggregates formed significantly more rapidly than the 
fibrils. This is the first indication that different partially folded 
intermediates may be responsible for different aggregation pathways (amorphous 
and fibrillar). The data support the hypothesis that amyloid fibril formation 
involves the ordered self-assembly of partially folded species that are critical 
soluble precursors of fibrils.