5ir3 | pdb_00005ir3
Crystal structure of the recombinant highest fibrillogenic natural mutant (obtained from patient AR) derived from lambda 6 light chain variable domain
Structural highlights
Function[LV657_HUMAN] V region of the variable domain of immunoglobulin light chains that participates in the antigen recognition (PubMed:24600447). Immunoglobulins, also known as antibodies, are membrane-bound or secreted glycoproteins produced by B lymphocytes. In the recognition phase of humoral immunity, the membrane-bound immunoglobulins serve as receptors which, upon binding of a specific antigen, trigger the clonal expansion and differentiation of B lymphocytes into immunoglobulins-secreting plasma cells. Secreted immunoglobulins mediate the effector phase of humoral immunity, which results in the elimination of bound antigens (PubMed:20176268, PubMed:22158414). The antigen binding site is formed by the variable domain of one heavy chain, together with that of its associated light chain. Thus, each immunoglobulin has two antigen binding sites with remarkable affinity for a particular antigen. The variable domains are assembled by a process called V-(D)-J rearrangement and can then be subjected to somatic hypermutations which, after exposure to antigen and selection, allow affinity maturation for a particular antigen (PubMed:17576170, PubMed:20176268).[1] [2] [3] [4] Publication Abstract from PubMedLight chain amyloidosis is a lethal disease where vital organs are damaged by the fibrillar aggregation of monoclonal light chains. lambda6a is an immunoglobulin light chain encoded by the germ line gene segment implicated in this disease. AR is a patient-derived germ line variant with a markedly low thermodynamic stability and prone to form fibrils in vitro in less than an hour. Here, we sought to stabilize this domain by mutating some residues back to the germ line sequence, and the most stabilizing mutations were the single mutant AR-F21I and the double mutant AR-F21/IV104L, both located in the hydrophobic core. While mutation Arg25Gly in 6aJL2 destabilized the domain, mutating Gly25 back to arginine in AR did not contribute to stabilization as expected. Crystallographic structures of AR and 6a-R25G were generated to explain this discrepancy. Finally, 6a-R25G crystals revealed an octameric assembly which was emulated into 6aJL2 and AR crystals by replicating their structural parameters and suggesting a common assembly pattern. This article is protected by copyright. All rights reserved. Stabilizing an amyloidogenic lambda6 light chain variable domain.,Luna-Martinez OD, Hernandez-Santoyo A, Villalba-Velazquez MI, Sanchez-Alcala R, Fernandez-Velasco DA, Becerril B FEBS J. 2017 Sep 12. doi: 10.1111/febs.14265. PMID:28898537[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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