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| | <StructureSection load='6sm1' size='340' side='right'caption='[[6sm1]], [[Resolution|resolution]] 1.55Å' scene=''> | | <StructureSection load='6sm1' size='340' side='right'caption='[[6sm1]], [[Resolution|resolution]] 1.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6sm1]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SM1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6SM1 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6sm1]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6SM1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6SM1 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.55Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4nki|4nki]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PGE:TRIETHYLENE+GLYCOL'>PGE</scene></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6sm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sm1 OCA], [http://pdbe.org/6sm1 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6sm1 RCSB], [http://www.ebi.ac.uk/pdbsum/6sm1 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6sm1 ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6sm1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6sm1 OCA], [https://pdbe.org/6sm1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6sm1 RCSB], [https://www.ebi.ac.uk/pdbsum/6sm1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6sm1 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LV214_HUMAN LV214_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).<ref>PMID:17576170</ref> <ref>PMID:20176268</ref> <ref>PMID:22158414</ref> <ref>PMID:24600447</ref> | + | [https://www.uniprot.org/uniprot/LV214_HUMAN LV214_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).<ref>PMID:17576170</ref> <ref>PMID:20176268</ref> <ref>PMID:22158414</ref> <ref>PMID:24600447</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 23: |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Buchner, J]] | + | [[Category: Buchner J]] |
| - | [[Category: Cendales, M D.P]] | + | [[Category: Cendales MDP]] |
| - | [[Category: Groll, M]] | + | [[Category: Groll M]] |
| - | [[Category: Hegenbart, U]] | + | [[Category: Hegenbart U]] |
| - | [[Category: Hunziger, L]] | + | [[Category: Hunziger L]] |
| - | [[Category: Kazman, P]] | + | [[Category: Kazman P]] |
| - | [[Category: Koehler, R]] | + | [[Category: Koehler R]] |
| - | [[Category: Schoenland, S]] | + | [[Category: Schoenland S]] |
| - | [[Category: Vielberg, M T]] | + | [[Category: Vielberg M-T]] |
| - | [[Category: Weber, B]] | + | [[Category: Weber B]] |
| - | [[Category: Zacharias, M]] | + | [[Category: Zacharias M]] |
| - | [[Category: Al amyloidosis]]
| + | |
| - | [[Category: Antibody folding]]
| + | |
| - | [[Category: Dynamic]]
| + | |
| - | [[Category: Immune system]]
| + | |
| - | [[Category: Protein stability]]
| + | |
| Structural highlights
Function
LV214_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 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[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Teng G, Papavasiliou FN. Immunoglobulin somatic hypermutation. Annu Rev Genet. 2007;41:107-20. PMID:17576170 doi:http://dx.doi.org/10.1146/annurev.genet.41.110306.130340
- ↑ Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S41-52. doi:, 10.1016/j.jaci.2009.09.046. PMID:20176268 doi:http://dx.doi.org/10.1016/j.jaci.2009.09.046
- ↑ McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2011 Dec 9;12(1):24-34. doi: 10.1038/nri3128. PMID:22158414 doi:http://dx.doi.org/10.1038/nri3128
- ↑ Lefranc MP. Immunoglobulin and T Cell Receptor Genes: IMGT((R)) and the Birth and Rise of Immunoinformatics. Front Immunol. 2014 Feb 5;5:22. doi: 10.3389/fimmu.2014.00022. eCollection 2014. PMID:24600447 doi:http://dx.doi.org/10.3389/fimmu.2014.00022
- ↑ Kazman P, Vielberg MT, Pulido Cendales MD, Hunziger L, Weber B, Hegenbart U, Zacharias M, Kohler R, Schonland S, Groll M, Buchner J. Fatal amyloid formation in a patient's antibody light chain is caused by a single point mutation. Elife. 2020 Mar 10;9. pii: 52300. doi: 10.7554/eLife.52300. PMID:32151314 doi:http://dx.doi.org/10.7554/eLife.52300
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