Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation
Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotox...
Gespeichert in:
| Veröffentlicht in: | Journal of molecular biology 2023-12, Vol.435 (24), p.168320-168320, Article 168320 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 168320 |
|---|---|
| container_issue | 24 |
| container_start_page | 168320 |
| container_title | Journal of molecular biology |
| container_volume | 435 |
| creator | Broggini, Luca Barzago, Maria Monica Speranzini, Valentina Schulte, Tim Sonzini, Federica Giono, Matteo Romeo, Margherita Milani, Paolo Caminito, Serena Mazzini, Giulia Rognoni, Paola Merlini, Giampaolo Pappone, Carlo Anastasia, Luigi Nuvolone, Mario Palladini, Giovanni Diomede, Luisa Ricagno, Stefano |
| description | Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 V
domain and stabilise an unexpected partially open LC dimer in which the two V
domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms. |
| doi_str_mv | 10.1016/j.jmb.2023.168320 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3040357911</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2880097204</sourcerecordid><originalsourceid>FETCH-LOGICAL-c329t-2b31ca9f288a8703ce2812e8897f69989d9dbf61d2bcedd640e759e5740428823</originalsourceid><addsrcrecordid>eNqFkb1u2zAURokiQeM4eYAuBccsci9J_ZBjETRNgKBdkpmgyCubhkS6JI3WefrKsNO107d85yyHkE8MVgxY-2W72k79igMXK9ZKweEDWTCQqpKtkBdkAcB5xaVor8h1zlsAaEQtP5Ir0cm24bJbkN8_TIh9dB4ztXEfCiZjCy0bpCX-8daXA40DNYGa6TBG7-Iag7d09OtNoXZjfKD9geZiej_6Nx_W1NCdScWbcZzRHQbq_IRpZmwMQ0yTKT6GG3I5mDHj7XmX5PXh28v9Y_X88_vT_dfnygquSsV7waxRA5fSyA6ERS4ZRylVN7RKSeWU64eWOd5bdK6tAbtGYdPVUM8MF0tyd_LuUvy1x1z05LPFcTQB4z5rATWIplOM_fc6-wBUx6Ger-x0tSnmnHDQu-Qnkw6agT6m0Vs9p9HHNPqUZmY-n_X7fkL3j3hvIf4CzjOMMw</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2880097204</pqid></control><display><type>article</type><title>Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation</title><source>MEDLINE</source><source>Elsevier ScienceDirect Journals</source><creator>Broggini, Luca ; Barzago, Maria Monica ; Speranzini, Valentina ; Schulte, Tim ; Sonzini, Federica ; Giono, Matteo ; Romeo, Margherita ; Milani, Paolo ; Caminito, Serena ; Mazzini, Giulia ; Rognoni, Paola ; Merlini, Giampaolo ; Pappone, Carlo ; Anastasia, Luigi ; Nuvolone, Mario ; Palladini, Giovanni ; Diomede, Luisa ; Ricagno, Stefano</creator><creatorcontrib>Broggini, Luca ; Barzago, Maria Monica ; Speranzini, Valentina ; Schulte, Tim ; Sonzini, Federica ; Giono, Matteo ; Romeo, Margherita ; Milani, Paolo ; Caminito, Serena ; Mazzini, Giulia ; Rognoni, Paola ; Merlini, Giampaolo ; Pappone, Carlo ; Anastasia, Luigi ; Nuvolone, Mario ; Palladini, Giovanni ; Diomede, Luisa ; Ricagno, Stefano</creatorcontrib><description>Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 V
domain and stabilise an unexpected partially open LC dimer in which the two V
domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.</description><identifier>ISSN: 0022-2836</identifier><identifier>EISSN: 1089-8638</identifier><identifier>DOI: 10.1016/j.jmb.2023.168320</identifier><identifier>PMID: 37865287</identifier><language>eng</language><publisher>Netherlands</publisher><subject>Amyloid - immunology ; amyloidosis ; Animals ; Caenorhabditis elegans ; cardiotoxicity ; domain ; heart ; Humans ; Immunoglobulin Light Chains - chemistry ; Immunoglobulin Light Chains - immunology ; Immunoglobulin Light Chains - therapeutic use ; Immunoglobulin Light-chain Amyloidosis - immunology ; Immunoglobulin Light-chain Amyloidosis - therapy ; immunoglobulins ; molecular biology ; Myocytes, Cardiac - metabolism ; patients ; prognosis ; protective effect ; Single-Domain Antibodies - chemistry ; Single-Domain Antibodies - immunology ; Single-Domain Antibodies - therapeutic use ; species ; therapeutics ; toxicity</subject><ispartof>Journal of molecular biology, 2023-12, Vol.435 (24), p.168320-168320, Article 168320</ispartof><rights>Copyright © 2023 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c329t-2b31ca9f288a8703ce2812e8897f69989d9dbf61d2bcedd640e759e5740428823</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37865287$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Broggini, Luca</creatorcontrib><creatorcontrib>Barzago, Maria Monica</creatorcontrib><creatorcontrib>Speranzini, Valentina</creatorcontrib><creatorcontrib>Schulte, Tim</creatorcontrib><creatorcontrib>Sonzini, Federica</creatorcontrib><creatorcontrib>Giono, Matteo</creatorcontrib><creatorcontrib>Romeo, Margherita</creatorcontrib><creatorcontrib>Milani, Paolo</creatorcontrib><creatorcontrib>Caminito, Serena</creatorcontrib><creatorcontrib>Mazzini, Giulia</creatorcontrib><creatorcontrib>Rognoni, Paola</creatorcontrib><creatorcontrib>Merlini, Giampaolo</creatorcontrib><creatorcontrib>Pappone, Carlo</creatorcontrib><creatorcontrib>Anastasia, Luigi</creatorcontrib><creatorcontrib>Nuvolone, Mario</creatorcontrib><creatorcontrib>Palladini, Giovanni</creatorcontrib><creatorcontrib>Diomede, Luisa</creatorcontrib><creatorcontrib>Ricagno, Stefano</creatorcontrib><title>Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation</title><title>Journal of molecular biology</title><addtitle>J Mol Biol</addtitle><description>Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 V
domain and stabilise an unexpected partially open LC dimer in which the two V
domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.</description><subject>Amyloid - immunology</subject><subject>amyloidosis</subject><subject>Animals</subject><subject>Caenorhabditis elegans</subject><subject>cardiotoxicity</subject><subject>domain</subject><subject>heart</subject><subject>Humans</subject><subject>Immunoglobulin Light Chains - chemistry</subject><subject>Immunoglobulin Light Chains - immunology</subject><subject>Immunoglobulin Light Chains - therapeutic use</subject><subject>Immunoglobulin Light-chain Amyloidosis - immunology</subject><subject>Immunoglobulin Light-chain Amyloidosis - therapy</subject><subject>immunoglobulins</subject><subject>molecular biology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>patients</subject><subject>prognosis</subject><subject>protective effect</subject><subject>Single-Domain Antibodies - chemistry</subject><subject>Single-Domain Antibodies - immunology</subject><subject>Single-Domain Antibodies - therapeutic use</subject><subject>species</subject><subject>therapeutics</subject><subject>toxicity</subject><issn>0022-2836</issn><issn>1089-8638</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkb1u2zAURokiQeM4eYAuBccsci9J_ZBjETRNgKBdkpmgyCubhkS6JI3WefrKsNO107d85yyHkE8MVgxY-2W72k79igMXK9ZKweEDWTCQqpKtkBdkAcB5xaVor8h1zlsAaEQtP5Ir0cm24bJbkN8_TIh9dB4ztXEfCiZjCy0bpCX-8daXA40DNYGa6TBG7-Iag7d09OtNoXZjfKD9geZiej_6Nx_W1NCdScWbcZzRHQbq_IRpZmwMQ0yTKT6GG3I5mDHj7XmX5PXh28v9Y_X88_vT_dfnygquSsV7waxRA5fSyA6ERS4ZRylVN7RKSeWU64eWOd5bdK6tAbtGYdPVUM8MF0tyd_LuUvy1x1z05LPFcTQB4z5rATWIplOM_fc6-wBUx6Ger-x0tSnmnHDQu-Qnkw6agT6m0Vs9p9HHNPqUZmY-n_X7fkL3j3hvIf4CzjOMMw</recordid><startdate>20231215</startdate><enddate>20231215</enddate><creator>Broggini, Luca</creator><creator>Barzago, Maria Monica</creator><creator>Speranzini, Valentina</creator><creator>Schulte, Tim</creator><creator>Sonzini, Federica</creator><creator>Giono, Matteo</creator><creator>Romeo, Margherita</creator><creator>Milani, Paolo</creator><creator>Caminito, Serena</creator><creator>Mazzini, Giulia</creator><creator>Rognoni, Paola</creator><creator>Merlini, Giampaolo</creator><creator>Pappone, Carlo</creator><creator>Anastasia, Luigi</creator><creator>Nuvolone, Mario</creator><creator>Palladini, Giovanni</creator><creator>Diomede, Luisa</creator><creator>Ricagno, Stefano</creator><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>7S9</scope><scope>L.6</scope></search><sort><creationdate>20231215</creationdate><title>Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation</title><author>Broggini, Luca ; Barzago, Maria Monica ; Speranzini, Valentina ; Schulte, Tim ; Sonzini, Federica ; Giono, Matteo ; Romeo, Margherita ; Milani, Paolo ; Caminito, Serena ; Mazzini, Giulia ; Rognoni, Paola ; Merlini, Giampaolo ; Pappone, Carlo ; Anastasia, Luigi ; Nuvolone, Mario ; Palladini, Giovanni ; Diomede, Luisa ; Ricagno, Stefano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c329t-2b31ca9f288a8703ce2812e8897f69989d9dbf61d2bcedd640e759e5740428823</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>Amyloid - immunology</topic><topic>amyloidosis</topic><topic>Animals</topic><topic>Caenorhabditis elegans</topic><topic>cardiotoxicity</topic><topic>domain</topic><topic>heart</topic><topic>Humans</topic><topic>Immunoglobulin Light Chains - chemistry</topic><topic>Immunoglobulin Light Chains - immunology</topic><topic>Immunoglobulin Light Chains - therapeutic use</topic><topic>Immunoglobulin Light-chain Amyloidosis - immunology</topic><topic>Immunoglobulin Light-chain Amyloidosis - therapy</topic><topic>immunoglobulins</topic><topic>molecular biology</topic><topic>Myocytes, Cardiac - metabolism</topic><topic>patients</topic><topic>prognosis</topic><topic>protective effect</topic><topic>Single-Domain Antibodies - chemistry</topic><topic>Single-Domain Antibodies - immunology</topic><topic>Single-Domain Antibodies - therapeutic use</topic><topic>species</topic><topic>therapeutics</topic><topic>toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Broggini, Luca</creatorcontrib><creatorcontrib>Barzago, Maria Monica</creatorcontrib><creatorcontrib>Speranzini, Valentina</creatorcontrib><creatorcontrib>Schulte, Tim</creatorcontrib><creatorcontrib>Sonzini, Federica</creatorcontrib><creatorcontrib>Giono, Matteo</creatorcontrib><creatorcontrib>Romeo, Margherita</creatorcontrib><creatorcontrib>Milani, Paolo</creatorcontrib><creatorcontrib>Caminito, Serena</creatorcontrib><creatorcontrib>Mazzini, Giulia</creatorcontrib><creatorcontrib>Rognoni, Paola</creatorcontrib><creatorcontrib>Merlini, Giampaolo</creatorcontrib><creatorcontrib>Pappone, Carlo</creatorcontrib><creatorcontrib>Anastasia, Luigi</creatorcontrib><creatorcontrib>Nuvolone, Mario</creatorcontrib><creatorcontrib>Palladini, Giovanni</creatorcontrib><creatorcontrib>Diomede, Luisa</creatorcontrib><creatorcontrib>Ricagno, Stefano</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>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Journal of molecular biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Broggini, Luca</au><au>Barzago, Maria Monica</au><au>Speranzini, Valentina</au><au>Schulte, Tim</au><au>Sonzini, Federica</au><au>Giono, Matteo</au><au>Romeo, Margherita</au><au>Milani, Paolo</au><au>Caminito, Serena</au><au>Mazzini, Giulia</au><au>Rognoni, Paola</au><au>Merlini, Giampaolo</au><au>Pappone, Carlo</au><au>Anastasia, Luigi</au><au>Nuvolone, Mario</au><au>Palladini, Giovanni</au><au>Diomede, Luisa</au><au>Ricagno, Stefano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation</atitle><jtitle>Journal of molecular biology</jtitle><addtitle>J Mol Biol</addtitle><date>2023-12-15</date><risdate>2023</risdate><volume>435</volume><issue>24</issue><spage>168320</spage><epage>168320</epage><pages>168320-168320</pages><artnum>168320</artnum><issn>0022-2836</issn><eissn>1089-8638</eissn><abstract>Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity in C. elegans in vivo model. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 V
domain and stabilise an unexpected partially open LC dimer in which the two V
domains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.</abstract><cop>Netherlands</cop><pmid>37865287</pmid><doi>10.1016/j.jmb.2023.168320</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2836 |
| ispartof | Journal of molecular biology, 2023-12, Vol.435 (24), p.168320-168320, Article 168320 |
| issn | 0022-2836 1089-8638 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_3040357911 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Amyloid - immunology amyloidosis Animals Caenorhabditis elegans cardiotoxicity domain heart Humans Immunoglobulin Light Chains - chemistry Immunoglobulin Light Chains - immunology Immunoglobulin Light Chains - therapeutic use Immunoglobulin Light-chain Amyloidosis - immunology Immunoglobulin Light-chain Amyloidosis - therapy immunoglobulins molecular biology Myocytes, Cardiac - metabolism patients prognosis protective effect Single-Domain Antibodies - chemistry Single-Domain Antibodies - immunology Single-Domain Antibodies - therapeutic use species therapeutics toxicity |
| title | Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-02T10%3A58%3A04IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nanobodies%20counteract%20the%20toxicity%20of%20an%20amyloidogenic%20light%20chain%20by%20stabilizing%20a%20partially%20open%20dimeric%20conformation&rft.jtitle=Journal%20of%20molecular%20biology&rft.au=Broggini,%20Luca&rft.date=2023-12-15&rft.volume=435&rft.issue=24&rft.spage=168320&rft.epage=168320&rft.pages=168320-168320&rft.artnum=168320&rft.issn=0022-2836&rft.eissn=1089-8638&rft_id=info:doi/10.1016/j.jmb.2023.168320&rft_dat=%3Cproquest_cross%3E2880097204%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2880097204&rft_id=info:pmid/37865287&rfr_iscdi=true |