ROLE OF THE LOCATION OF MUTATIONS IN LIGHT CHAIN AMYLOIDOSIS

Light Chain Amyloidosis results from unstable immunoglobulin light chains due to the proliferaton of monoclonal plasma B cells, which secrete monoclonal immunoclogulin light chains. These monoclonal immunoglobulin light chains are responsible for the characteristic pathological features found in patients with light chain related diseases that include Multiple Myeloma (MM) and Light Chain Amyloidosis (AL).

AL is characterized by the deposition of immunoglobulin light chains as amyloid fibrils in vital organs leading to organ failure and death. The organ most frequently affected is the kidney followed by the heart and liver. MM is characterized by bone lesions, hypercalcemia, renal failure, and anemia. These proteins contain mutations when when they are compared to their germline sequence. However, the location of these mutations in the N and C terminus, mutations in the beta hairpin and mutations in dimer interface.

We are interested in studying the effect the different mutations in the AL proteins have on the secondary structure, protein folding and stability and in amyloid formation. We use a kappa MM non-amyloidogenic protein as our control. We have followed protein unfolding by thermal and chemical denaturation using Circular Dichroism and Fluorescence spectroscopy. Amyloid fibril formation has been carried out at the melting temperature of the proteins and verified by Thioflavine T binding and electron microscopy. We have found the MM protein to be the most thermodynamically stable protein compared to the AL proteins.

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