6sm2 | pdb_00006sm2

Mutant immunoglobulin light chain causing amyloidosis (Pat-1)

spinqualitylabelsall models 6sm2, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6sm2 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 6sm1 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed In systemic light chain amyloidosis, an overexpressed antibody light chain (LC) forms fibrils which deposit in organs and cause their failure. While it is well-established that mutations in the LC's VL domain are important prerequisites, the mechanisms which render a patient LC amyloidogenic are ill-defined. In this study, we performed an in-depth analysis of the factors and mutations responsible for the pathogenic transformation of a patient-derived lambda LC, by recombinantly expressing variants in E. coli. We show that proteolytic cleavage of the patient LC resulting in an isolated VL domain is essential for fibril formation. Out of 11 mutations in the patient VL, only one, a leucine to valine mutation, is responsible for fibril formation. It disrupts a hydrophobic network rendering the C-terminal segment of VL more dynamic and decreasing domain stability. Thus, the combination of proteolytic cleavage and the destabilizing mutation trigger conformational changes that turn the LC pathogenic. Fatal amyloid formation in a patient's antibody light chain is caused by a single point mutation.,Kazman P, Vielberg MT, Pulido Cendales MD, Hunziger L, Weber B, Hegenbart U, Zacharias M, Kohler R, Schonland S, Groll M, Buchner J Elife. 2020 Mar 10;9. pii: 52300. doi: 10.7554/eLife.52300. PMID:32151314 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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