• Julian Baur, Natalie Berghaus, Sarah Schreiner, Ute Hegenbart, Stefan O Schönland, Sebastian Wiese, Stefanie Huhn, and Christian Haupt.
• Institute of Protein Biochemistry, Ulm University, Ulm, Germany.
• Amyloid. 2023 Mar 1; 30 (1): 273727-37.

BackgroundSystemic AL amyloidosis arises from the misfolding of patient-specific immunoglobulin light chains (LCs). Potential drivers of LC amyloid formation are mutational changes and post-translational modifications (PTMs). However, little information is available on the exact primary structure of the AL proteins and their precursor LCs.ObjectiveWe analyse the exact primary structure of AL proteins extracted from 10 λ AL amyloidosis patients and their corresponding precursor LCs.Materials And MethodsBy cDNA sequencing of the precursor LC genes in combination with mass spectrometry of the AL proteins, the exact primary structure and PTMs were determined. This information was used to analyse their biochemical properties.ResultsAll AL proteins comprise the VL and a small part of the CL with a common C-terminal truncation region. While all AL proteins retain the conserved native disulphide bond of the VL, we found no evidence for presence of other common PTMs. The analysis of the biochemical properties revealed that the isoelectric point of the VL is significantly increased due to introduced mutations.ConclusionOur data imply that mutational changes influence the surface charge properties of the VL and that common proteolytic processes are involved in the generation of the cleavage sites of AL proteins.

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