Driving forces in amyloidosis: How does a light chain make a heavy heart?

Daniel E Otzen

doi:10.1016/j.jbc.2021.100785

Abstract

Light-chain amyloidosis (AL) is a fatal disorder wherein the immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the light chain variable domain (VL) are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the VL of a patient with cardiac AL. Their data suggest that decreased VL stability and increased flexibility in the core of the VL, caused by mutations outside of this core, could be key to aggregation and highlight the delicate balancing act required for antibody maturation to enable antigen recognition while not altering protein biophysics.

Highlights

Amyloidosis is a rare disorder caused by the misfolding of soluble amyloid protein, with the resulting aggregates interfering with organ function
Decades of research on protein structure and folding have led to the generalization that mutations to the hydrophobic core of a wellpacked protein are the most destabilizing, and one would not expect loop residues to affect stability as much as framework mutations
The relatively low number of mutations in this case made it straightforward for the researchers to dissect the impact of each change and ask how much change is required to stimulate fibril formation, what molecular properties of the proteins are affected by these mutations, and how are they linked with aggregation?

Summary

Introduction

Amyloidosis is a rare disorder caused by the misfolding of soluble amyloid protein, with the resulting aggregates interfering with organ function. Decades of research on protein structure and folding have led to the generalization that mutations to the hydrophobic core of a wellpacked protein are the most destabilizing, and one would not expect loop residues to affect stability as much as framework mutations. The relatively low number of mutations in this case made it straightforward for the researchers to dissect the impact of each change and ask how much change (i.e., how many mutations) is required to stimulate fibril formation, what molecular properties of the proteins are affected by these mutations, and how are they linked with aggregation?

Results

Conclusion