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Dissection of the molecular fibril formation pathway of patient-derived light chain variants

Subject Area Biochemistry
Term from 2019 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 410477202
 
Previous research suggested that amyloidogenic light chains show a reduced stability and/or susceptibility to protease digestion. In this project we will analyze the protein folding and misfolding properties of light chains and their fragments associated with two major clinical phenotypes of AL amyloidosis that present either dominant heart or kidney involvement. The detailed aims will be: (i) Generation of a high-throughput recombinant expression system for human pathogenic full-length light chains and their fragments. (ii) Analyze the role of sequence variations on fibril formation. (iii) Elucidation of plasma proteases cleaving AL light chains and the impact of plasma factors affecting fibril formation. Through this work we will test the hypothesis that there are various conserved mechanisms how intrinsic sequence variations and proteolytic processing render light chain variants amyloidogenic. Our project will provide a data set for a large number of patient-derived mutations concerning their effects on fibril formation in the context of the light chain fragments or the entire light chain. Together with our data on extrinsic factors effecting amyloidosis and the patient data, the proposed detailed mechanistic analyses will reveal general principles which turn stable immunoglobulin domains into fibrils which could result in new treatment options.
DFG Programme Research Units
 
 

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