Concurrent structural and biophysical traits link with immunoglobulin light chains amyloid propensity

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Light chain amyloidosis (AL) is the most common systemic amyloidosis.
• It arises from the overproduction and aggregation of monoclonal immunoglobulin light chains (LCs).
• The molecular drivers of LC aggregation and toxicity are complex due to patient-specific LC variations.

Purpose of the Study:

• To identify generalizable molecular determinants of amyloidogenic light chain (LC) propensity.
• To characterize sequence-diverse LCs to understand aggregation mechanisms.
• To provide data for designing synthetic inhibitors of LC aggregation.

Main Methods:

• Systematic characterization of thirteen sequence-diverse full-length LCs (eight amyloidogenic, five non-amyloidogenic).
• Utilized spectroscopic techniques, limited proteolysis, and X-ray crystallography.
• Determined seven crystal structures of LCs.

Main Results:

• Low fold stability and high protein dynamics correlate with amyloidogenic LCs.
• Hydrophobicity, structural rearrangements, and dimeric interface characteristics did not significantly predict amyloid propensity.
• Identified shared biophysical properties associated with LC aggregation.

Conclusions:

• Low fold stability and high dynamics are key indicators of amyloidogenic LC behavior.
• These findings offer insights into the fundamental mechanisms of AL amyloidogenesis.
• The data will be crucial for developing novel therapeutic strategies targeting LC aggregation.