Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity
Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the stru...
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| creator | Lee, Kwangkook Gu, Shenyan Jin, Lei Le, Thi Tuc Nghi Cheng, Luisa W Strotmeier, Jasmin Kruel, Anna Magdalena Yao, Guorui Perry, Kay Rummel, Andreas Jin, Rongsheng |
| description | Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the structure of a ∼760 kDa 14-subunit large PTC of serotype A (L-PTC/A) and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry. |
| doi_str_mv | 10.1371/journal.ppat.1003690 |
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Erec</contributor><creatorcontrib>Lee, Kwangkook ; Gu, Shenyan ; Jin, Lei ; Le, Thi Tuc Nghi ; Cheng, Luisa W ; Strotmeier, Jasmin ; Kruel, Anna Magdalena ; Yao, Guorui ; Perry, Kay ; Rummel, Andreas ; Jin, Rongsheng ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS) ; Stebbins, C. Erec</creatorcontrib><description>Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the structure of a ∼760 kDa 14-subunit large PTC of serotype A (L-PTC/A) and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1003690</identifier><identifier>PMID: 24130488</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Binding sites ; Botulinum Toxins - chemistry ; Botulinum Toxins - genetics ; Botulinum Toxins - toxicity ; Botulism ; Carbohydrates ; Clostridium botulinum ; Clostridium botulinum - genetics ; Clostridium botulinum - metabolism ; Female ; Health aspects ; Host-parasite relationships ; Mice ; Microbiology ; Microscopy ; Multiprotein Complexes - chemistry ; Multiprotein Complexes - genetics ; Multiprotein Complexes - toxicity ; Neurotoxic agents ; Physiological aspects ; Poisons ; Protein Structure, Quaternary ; Proteins ; Structure-Activity Relationship ; Toxicity</subject><ispartof>PLoS Patho, 2013-10, Vol.9 (10), p.e1003690</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Lee et al 2013 Lee et al</rights><rights>2013 Lee et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Lee K, Gu S, Jin L, Le TTN, Cheng LW, et al. (2013) Structure of a Bimodular Botulinum Neurotoxin Complex Provides Insights into Its Oral Toxicity. 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Erec</contributor><creatorcontrib>Lee, Kwangkook</creatorcontrib><creatorcontrib>Gu, Shenyan</creatorcontrib><creatorcontrib>Jin, Lei</creatorcontrib><creatorcontrib>Le, Thi Tuc Nghi</creatorcontrib><creatorcontrib>Cheng, Luisa W</creatorcontrib><creatorcontrib>Strotmeier, Jasmin</creatorcontrib><creatorcontrib>Kruel, Anna Magdalena</creatorcontrib><creatorcontrib>Yao, Guorui</creatorcontrib><creatorcontrib>Perry, Kay</creatorcontrib><creatorcontrib>Rummel, Andreas</creatorcontrib><creatorcontrib>Jin, Rongsheng</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity</title><title>PLoS Patho</title><addtitle>PLoS Pathog</addtitle><description>Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. 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We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry.</description><subject>Animals</subject><subject>Binding sites</subject><subject>Botulinum Toxins - chemistry</subject><subject>Botulinum Toxins - genetics</subject><subject>Botulinum Toxins - toxicity</subject><subject>Botulism</subject><subject>Carbohydrates</subject><subject>Clostridium botulinum</subject><subject>Clostridium botulinum - genetics</subject><subject>Clostridium botulinum - metabolism</subject><subject>Female</subject><subject>Health aspects</subject><subject>Host-parasite relationships</subject><subject>Mice</subject><subject>Microbiology</subject><subject>Microscopy</subject><subject>Multiprotein Complexes - chemistry</subject><subject>Multiprotein Complexes - genetics</subject><subject>Multiprotein Complexes - toxicity</subject><subject>Neurotoxic agents</subject><subject>Physiological aspects</subject><subject>Poisons</subject><subject>Protein Structure, Quaternary</subject><subject>Proteins</subject><subject>Structure-Activity Relationship</subject><subject>Toxicity</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkl2L1DAUhoso7jr6D0SLXnkxY9J8tTcLy-LHwKLg6q0hzcdMhjYpSbrM_ntTO7tswRsJJIeT57xJ3pyieA3BBiIGPx78GJzoNsMg0gYCgGgDnhTnkBC0Zojhp4_is-JFjAcAMESQPi_OqhwAXNfnxe-bFEaZxqBLb0pRtrb3auxEKFufxs66sS-dHoNP_mhdKX0_dPpYDsHfWqVjaV20u32aguRLmwMfRFdOtLTp7mXxzIgu6lendVX8-vzp59XX9fX3L9ury-u1pBSkdc0IFgjmCWoNsEFNywxpKGlNTbGRjWlpZWpmqkppyhAVkmLYAKUgUFBWaFW8nXWHzkd-siZyiEndoIrmaVVsZ0J5ceBDsL0Id9wLy_8mfNhxEZKVneYNlERmg0jdthiQtoatYpXKdyAGGaCz1sXptLHttZLapfzohehyx9k93_lbjlhDAAZZ4N0s4GOyPGantNxL75yWiUPQUEqnN72foZ3Il7LO-Kwlexslv0QENpgQyDK1-QeVh9K9zZLa2JxfFHxYFGQm6WPaiTFGvr358R_styWLZ1YGH2PQ5sEPCPjUsfffwqeO5aeOzWVvHnv5UHTfougPh4bo9Q</recordid><startdate>20131001</startdate><enddate>20131001</enddate><creator>Lee, Kwangkook</creator><creator>Gu, Shenyan</creator><creator>Jin, Lei</creator><creator>Le, Thi Tuc Nghi</creator><creator>Cheng, Luisa W</creator><creator>Strotmeier, Jasmin</creator><creator>Kruel, Anna Magdalena</creator><creator>Yao, Guorui</creator><creator>Perry, Kay</creator><creator>Rummel, Andreas</creator><creator>Jin, Rongsheng</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>ISN</scope><scope>ISR</scope><scope>OTOTI</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131001</creationdate><title>Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity</title><author>Lee, Kwangkook ; Gu, Shenyan ; Jin, Lei ; Le, Thi Tuc Nghi ; Cheng, Luisa W ; Strotmeier, Jasmin ; Kruel, Anna Magdalena ; Yao, Guorui ; Perry, Kay ; Rummel, Andreas ; Jin, Rongsheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c660t-8754a3154a1ee04f39b7f5965bf864fc9fb62f87f22de6736ac64190dd10d1c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Binding sites</topic><topic>Botulinum Toxins - chemistry</topic><topic>Botulinum Toxins - genetics</topic><topic>Botulinum Toxins - toxicity</topic><topic>Botulism</topic><topic>Carbohydrates</topic><topic>Clostridium botulinum</topic><topic>Clostridium botulinum - genetics</topic><topic>Clostridium botulinum - metabolism</topic><topic>Female</topic><topic>Health aspects</topic><topic>Host-parasite relationships</topic><topic>Mice</topic><topic>Microbiology</topic><topic>Microscopy</topic><topic>Multiprotein Complexes - chemistry</topic><topic>Multiprotein Complexes - genetics</topic><topic>Multiprotein Complexes - toxicity</topic><topic>Neurotoxic agents</topic><topic>Physiological aspects</topic><topic>Poisons</topic><topic>Protein Structure, Quaternary</topic><topic>Proteins</topic><topic>Structure-Activity Relationship</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lee, Kwangkook</creatorcontrib><creatorcontrib>Gu, Shenyan</creatorcontrib><creatorcontrib>Jin, Lei</creatorcontrib><creatorcontrib>Le, Thi Tuc Nghi</creatorcontrib><creatorcontrib>Cheng, Luisa W</creatorcontrib><creatorcontrib>Strotmeier, Jasmin</creatorcontrib><creatorcontrib>Kruel, Anna Magdalena</creatorcontrib><creatorcontrib>Yao, Guorui</creatorcontrib><creatorcontrib>Perry, Kay</creatorcontrib><creatorcontrib>Rummel, Andreas</creatorcontrib><creatorcontrib>Jin, Rongsheng</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>OSTI.GOV</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS Patho</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lee, Kwangkook</au><au>Gu, Shenyan</au><au>Jin, Lei</au><au>Le, Thi Tuc Nghi</au><au>Cheng, Luisa W</au><au>Strotmeier, Jasmin</au><au>Kruel, Anna Magdalena</au><au>Yao, Guorui</au><au>Perry, Kay</au><au>Rummel, Andreas</au><au>Jin, Rongsheng</au><au>Stebbins, C. Erec</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity</atitle><jtitle>PLoS Patho</jtitle><addtitle>PLoS Pathog</addtitle><date>2013-10-01</date><risdate>2013</risdate><volume>9</volume><issue>10</issue><spage>e1003690</spage><pages>e1003690-</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Botulinum neurotoxins (BoNTs) are produced by Clostridium botulinum and cause the fatal disease botulism, a flaccid paralysis of the muscle. BoNTs are released together with several auxiliary proteins as progenitor toxin complexes (PTCs) to become highly potent oral poisons. Here, we report the structure of a ∼760 kDa 14-subunit large PTC of serotype A (L-PTC/A) and reveal insight into its absorption mechanism. Using a combination of X-ray crystallography, electron microscopy, and functional studies, we found that L-PTC/A consists of two structurally and functionally independent sub-complexes. A hetero-dimeric 290 kDa complex protects BoNT, while a hetero-dodecameric 470 kDa complex facilitates its absorption in the harsh environment of the gastrointestinal tract. BoNT absorption is mediated by nine glycan-binding sites on the dodecameric sub-complex that forms multivalent interactions with carbohydrate receptors on intestinal epithelial cells. We identified monosaccharides that blocked oral BoNT intoxication in mice, which suggests a new strategy for the development of preventive countermeasures for BoNTs based on carbohydrate receptor mimicry.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24130488</pmid><doi>10.1371/journal.ppat.1003690</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Binding sites Botulinum Toxins - chemistry Botulinum Toxins - genetics Botulinum Toxins - toxicity Botulism Carbohydrates Clostridium botulinum Clostridium botulinum - genetics Clostridium botulinum - metabolism Female Health aspects Host-parasite relationships Mice Microbiology Microscopy Multiprotein Complexes - chemistry Multiprotein Complexes - genetics Multiprotein Complexes - toxicity Neurotoxic agents Physiological aspects Poisons Protein Structure, Quaternary Proteins Structure-Activity Relationship Toxicity |
| title | Structure of a bimodular botulinum neurotoxin complex provides insights into its oral toxicity |
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