Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis
Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the pro...
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| Veröffentlicht in: | Biochemistry (Easton) 2015-08, Vol.54 (32), p.4978-4986 |
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| container_title | Biochemistry (Easton) |
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| creator | Pelaez-Aguilar, Angel E Rivillas-Acevedo, Lina French-Pacheco, Leidys Valdes-Garcia, Gilberto Maya-Martinez, Roberto Pastor, Nina Amero, Carlos |
| description | Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis. Furthermore, using nuclear magnetic resonance spectroscopy, dynamic light scattering, and isothermal titration calorimetry, we have determined that the inhibition is due to binding to the protein in its native state, interacting mainly with aromatic residues. |
| doi_str_mv | 10.1021/acs.biochem.5b00288 |
| format | Article |
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Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis. Furthermore, using nuclear magnetic resonance spectroscopy, dynamic light scattering, and isothermal titration calorimetry, we have determined that the inhibition is due to binding to the protein in its native state, interacting mainly with aromatic residues.</description><identifier>ISSN: 0006-2960</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/acs.biochem.5b00288</identifier><identifier>PMID: 26214579</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amino Acid Sequence ; Amino Acid Substitution ; Amyloid - antagonists & inhibitors ; Amyloid - biosynthesis ; Amyloid - genetics ; Amyloidosis - drug therapy ; Amyloidosis - genetics ; Amyloidosis - metabolism ; Catechin - analogs & derivatives ; Catechin - pharmacology ; Humans ; Immunoglobulin Light Chains - biosynthesis ; Immunoglobulin Light Chains - drug effects ; Immunoglobulin Light Chains - genetics ; In Vitro Techniques ; Melatonin - pharmacology ; Microscopy, Electron, Transmission ; Models, Molecular ; Molecular Sequence Data ; Mutation, Missense ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding - drug effects ; Protein Multimerization - drug effects ; Quercetin - pharmacology ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - drug effects ; Recombinant Proteins - genetics ; Rifampin - pharmacology ; Tetracycline - pharmacology</subject><ispartof>Biochemistry (Easton), 2015-08, Vol.54 (32), p.4978-4986</ispartof><rights>Copyright © 2015 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a378t-f95b339d3b72aceb17bc3ee5a03d8beb877d2e62e8ecb561d4978f584fd0824a3</citedby><cites>FETCH-LOGICAL-a378t-f95b339d3b72aceb17bc3ee5a03d8beb877d2e62e8ecb561d4978f584fd0824a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.biochem.5b00288$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.biochem.5b00288$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2763,27075,27923,27924,56737,56787</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26214579$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pelaez-Aguilar, Angel E</creatorcontrib><creatorcontrib>Rivillas-Acevedo, Lina</creatorcontrib><creatorcontrib>French-Pacheco, Leidys</creatorcontrib><creatorcontrib>Valdes-Garcia, Gilberto</creatorcontrib><creatorcontrib>Maya-Martinez, Roberto</creatorcontrib><creatorcontrib>Pastor, Nina</creatorcontrib><creatorcontrib>Amero, Carlos</creatorcontrib><title>Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis</title><title>Biochemistry (Easton)</title><addtitle>Biochemistry</addtitle><description>Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis. Furthermore, using nuclear magnetic resonance spectroscopy, dynamic light scattering, and isothermal titration calorimetry, we have determined that the inhibition is due to binding to the protein in its native state, interacting mainly with aromatic residues.</description><subject>Amino Acid Sequence</subject><subject>Amino Acid Substitution</subject><subject>Amyloid - antagonists & inhibitors</subject><subject>Amyloid - biosynthesis</subject><subject>Amyloid - genetics</subject><subject>Amyloidosis - drug therapy</subject><subject>Amyloidosis - genetics</subject><subject>Amyloidosis - metabolism</subject><subject>Catechin - analogs & derivatives</subject><subject>Catechin - pharmacology</subject><subject>Humans</subject><subject>Immunoglobulin Light Chains - biosynthesis</subject><subject>Immunoglobulin Light Chains - drug effects</subject><subject>Immunoglobulin Light Chains - genetics</subject><subject>In Vitro Techniques</subject><subject>Melatonin - pharmacology</subject><subject>Microscopy, Electron, Transmission</subject><subject>Models, Molecular</subject><subject>Molecular Sequence Data</subject><subject>Mutation, Missense</subject><subject>Nuclear Magnetic Resonance, Biomolecular</subject><subject>Protein Binding - drug effects</subject><subject>Protein Multimerization - drug effects</subject><subject>Quercetin - pharmacology</subject><subject>Recombinant Proteins - biosynthesis</subject><subject>Recombinant Proteins - drug effects</subject><subject>Recombinant Proteins - genetics</subject><subject>Rifampin - pharmacology</subject><subject>Tetracycline - pharmacology</subject><issn>0006-2960</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkV1LwzAUhoMoOqe_QJBeetN58tUkl2O4ORkIotclaVKbsTbadMj-vZ2rgjfi1eHA87wHzovQFYYJBoJvdREnxoeicvWEGwAi5REaYU4gZUrxYzQCgCwlKoMzdB7jul8ZCHaKzkhGMONCjZBdNpU3vvOhSUKZrPxr1SWzSvsmyfTDiqRPhC2Sab3bBG-TuTeuTeahrfWXMY0xFF53ziYfvqt-6YMToo8X6KTUm-guhzlGL_O759l9unpcLGfTVaqpkF1aKm4oVZYaQXThDBamoM5xDdRK44wUwhKXESddYXiGLVNCllyy0oIkTNMxujnkvrXhfetil9c-Fm6z0Y0L25hjgQVTGBT8AwXOBKVAe5Qe0KINMbauzN9aX-t2l2PI903kfRP50EQ-NNFb18OBramd_XG-X98Dtwdgb6_Dtm361_wZ-QlFDJZv</recordid><startdate>20150818</startdate><enddate>20150818</enddate><creator>Pelaez-Aguilar, Angel E</creator><creator>Rivillas-Acevedo, Lina</creator><creator>French-Pacheco, Leidys</creator><creator>Valdes-Garcia, Gilberto</creator><creator>Maya-Martinez, Roberto</creator><creator>Pastor, Nina</creator><creator>Amero, Carlos</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope></search><sort><creationdate>20150818</creationdate><title>Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis</title><author>Pelaez-Aguilar, Angel E ; Rivillas-Acevedo, Lina ; French-Pacheco, Leidys ; Valdes-Garcia, Gilberto ; Maya-Martinez, Roberto ; Pastor, Nina ; Amero, Carlos</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a378t-f95b339d3b72aceb17bc3ee5a03d8beb877d2e62e8ecb561d4978f584fd0824a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Amino Acid Sequence</topic><topic>Amino Acid Substitution</topic><topic>Amyloid - antagonists & inhibitors</topic><topic>Amyloid - biosynthesis</topic><topic>Amyloid - genetics</topic><topic>Amyloidosis - drug therapy</topic><topic>Amyloidosis - genetics</topic><topic>Amyloidosis - metabolism</topic><topic>Catechin - analogs & derivatives</topic><topic>Catechin - pharmacology</topic><topic>Humans</topic><topic>Immunoglobulin Light Chains - biosynthesis</topic><topic>Immunoglobulin Light Chains - drug effects</topic><topic>Immunoglobulin Light Chains - genetics</topic><topic>In Vitro Techniques</topic><topic>Melatonin - pharmacology</topic><topic>Microscopy, Electron, Transmission</topic><topic>Models, Molecular</topic><topic>Molecular Sequence Data</topic><topic>Mutation, Missense</topic><topic>Nuclear Magnetic Resonance, Biomolecular</topic><topic>Protein Binding - drug effects</topic><topic>Protein Multimerization - drug effects</topic><topic>Quercetin - pharmacology</topic><topic>Recombinant Proteins - biosynthesis</topic><topic>Recombinant Proteins - drug effects</topic><topic>Recombinant Proteins - genetics</topic><topic>Rifampin - pharmacology</topic><topic>Tetracycline - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pelaez-Aguilar, Angel E</creatorcontrib><creatorcontrib>Rivillas-Acevedo, Lina</creatorcontrib><creatorcontrib>French-Pacheco, Leidys</creatorcontrib><creatorcontrib>Valdes-Garcia, Gilberto</creatorcontrib><creatorcontrib>Maya-Martinez, Roberto</creatorcontrib><creatorcontrib>Pastor, Nina</creatorcontrib><creatorcontrib>Amero, Carlos</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pelaez-Aguilar, Angel E</au><au>Rivillas-Acevedo, Lina</au><au>French-Pacheco, Leidys</au><au>Valdes-Garcia, Gilberto</au><au>Maya-Martinez, Roberto</au><au>Pastor, Nina</au><au>Amero, Carlos</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2015-08-18</date><risdate>2015</risdate><volume>54</volume><issue>32</issue><spage>4978</spage><epage>4986</epage><pages>4978-4986</pages><issn>0006-2960</issn><eissn>1520-4995</eissn><abstract>Light chain amyloidosis (AL) is a deadly disease characterized by the deposition of monoclonal immunoglobulin light chains as insoluble amyloid fibrils in different organs and tissues. Germ line λ VI has been closely related to this condition; moreover, the R24G mutation is present in 25% of the proteins of this germ line in AL patients. In this work, five small molecules were tested as inhibitors of the formation of amyloid fibrils from the 6aJL2-R24G protein. We have found by thioflavin T fluorescence and transmission electron microscopy that EGCG inhibits 6aJL2-R24G fibrillogenesis. Furthermore, using nuclear magnetic resonance spectroscopy, dynamic light scattering, and isothermal titration calorimetry, we have determined that the inhibition is due to binding to the protein in its native state, interacting mainly with aromatic residues.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>26214579</pmid><doi>10.1021/acs.biochem.5b00288</doi><tpages>9</tpages></addata></record> |
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| subjects | Amino Acid Sequence Amino Acid Substitution Amyloid - antagonists & inhibitors Amyloid - biosynthesis Amyloid - genetics Amyloidosis - drug therapy Amyloidosis - genetics Amyloidosis - metabolism Catechin - analogs & derivatives Catechin - pharmacology Humans Immunoglobulin Light Chains - biosynthesis Immunoglobulin Light Chains - drug effects Immunoglobulin Light Chains - genetics In Vitro Techniques Melatonin - pharmacology Microscopy, Electron, Transmission Models, Molecular Molecular Sequence Data Mutation, Missense Nuclear Magnetic Resonance, Biomolecular Protein Binding - drug effects Protein Multimerization - drug effects Quercetin - pharmacology Recombinant Proteins - biosynthesis Recombinant Proteins - drug effects Recombinant Proteins - genetics Rifampin - pharmacology Tetracycline - pharmacology |
| title | Inhibition of Light Chain 6aJL2-R24G Amyloid Fiber Formation Associated with Light Chain Amyloidosis |
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