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| | ==Crystal structure of the unstable and highly fibrillogenic Pro7Ser mutant of the Recombinant variable domain 6AJL2== | | ==Crystal structure of the unstable and highly fibrillogenic Pro7Ser mutant of the Recombinant variable domain 6AJL2== |
| - | <StructureSection load='3bdx' size='340' side='right' caption='[[3bdx]], [[Resolution|resolution]] 2.30Å' scene=''> | + | <StructureSection load='3bdx' size='340' side='right'caption='[[3bdx]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3bdx]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BDX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3BDX FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3bdx]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3BDX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3BDX FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MES:2-(N-MORPHOLINO)-ETHANESULFONIC+ACID'>MES</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VL gene segment 6a and JL2/3 gene segment ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">VL gene segment 6a and JL2/3 gene segment ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3bdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bdx OCA], [http://pdbe.org/3bdx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3bdx RCSB], [http://www.ebi.ac.uk/pdbsum/3bdx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3bdx 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=3bdx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3bdx OCA], [https://pdbe.org/3bdx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3bdx RCSB], [https://www.ebi.ac.uk/pdbsum/3bdx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3bdx ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Human]] | | [[Category: Human]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Becerril, B]] | | [[Category: Becerril, B]] |
| | [[Category: Fuentes-Silva, D]] | | [[Category: Fuentes-Silva, D]] |
| Structural highlights
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Systemic amyloid light-chain (LC) amyloidosis is a disease process characterized by the pathological deposition of monoclonal LCs in tissue. All LC subtypes are capable of fibril formation although lambda chains, particularly those belonging to the lambda6 type, are overrepresented. Here, we report the thermodynamic and in vitro fibrillogenic properties of several mutants of the lambda6 protein 6aJL2 in which Pro7 and/or His8 was substituted by Ser or Pro. The H8P and H8S mutants were almost as stable as the wild-type protein and were poorly fibrillogenic. In contrast, the P7S mutation decreased the thermodynamic stability of 6aJL2 and greatly enhanced its capacity to form amyloid-like fibrils in vitro. The crystal structure of the P7S mutant showed that the substitution induced both local and long-distance effects, such as the rearrangement of the V(L) (variable region of the light chain)-V(L) interface. This mutant crystallized in two orthorhombic polymorphs, P2(1)2(1)2(1) and C222(1). In the latter, a monomer that was not arranged in the typical Bence-Jones dimer was observed for the first time. Crystal-packing analysis of the C222(1) lattice showed the establishment of intermolecular beta-beta interactions that involved the N-terminus and beta-strand B and that these could be relevant in the mechanism of LC fibril formation. Our results strongly suggest that Pro7 is a key residue in the conformation of the N-terminal sheet switch motif and, through long-distance interactions, is also critically involved in the contacts that stabilized the V(L) interface in lambda6 LCs.
A single mutation at the sheet switch region results in conformational changes favoring lambda6 light-chain fibrillogenesis.,Hernandez-Santoyo A, del Pozo Yauner L, Fuentes-Silva D, Ortiz E, Rudino-Pinera E, Sanchez-Lopez R, Horjales E, Becerril B, Rodriguez-Romero A J Mol Biol. 2010 Feb 19;396(2):280-92. Epub 2009 Nov 24. PMID:19941869[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hernandez-Santoyo A, del Pozo Yauner L, Fuentes-Silva D, Ortiz E, Rudino-Pinera E, Sanchez-Lopez R, Horjales E, Becerril B, Rodriguez-Romero A. A single mutation at the sheet switch region results in conformational changes favoring lambda6 light-chain fibrillogenesis. J Mol Biol. 2010 Feb 19;396(2):280-92. Epub 2009 Nov 24. PMID:19941869 doi:10.1016/j.jmb.2009.11.038
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