A conformational fingerprint for amyloidogenic light chains
Cristina Paissoni1, Sarita Puri1,2, Luca Broggini3
1Department of Bioscience, University of Milan, Milan, Italy.
Elife
|March 3, 2025
Summary
Immunoglobulin light-chain (LC) amyloidosis (AL) LCs misfold into toxic species, unlike multiple myeloma (MM) LCs. This study identified a distinct straight LC conformation in AL amyloidosis, crucial for drug development.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Medicine
Background:
- Immunoglobulin light-chain (LC) amyloidosis (AL) and multiple myeloma (MM) involve clonal LC overproduction.
- AL LCs misfold into toxic aggregates, causing organ damage, while MM LCs remain soluble.
Purpose of the Study:
- To identify a unique conformational fingerprint distinguishing AL amyloidosis LCs from multiple myeloma LCs.
- To understand the structural basis of LC aggregation in AL amyloidosis.
Main Methods:
- Small-angle X-ray scattering (SAXS) under native conditions.
- Molecular dynamics simulations.
- Hydrogen-deuterium exchange mass spectrometry.
Main Results:
- AL LCs showed greater conformational dynamics and deviations from known structures compared to MM LCs.
- A distinct, low-populated straight conformation (H state) was identified in AL LCs, maximizing solvent accessibility.
- The H state in AL LCs was experimentally validated.
Conclusions:
- A specific conformational ensemble, including the H state, differentiates AL amyloidosis LCs from MM LCs.
- This structural understanding provides a target for developing novel therapeutics for AL amyloidosis.
