Celeste M Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D Kjelgaard, Maren Watkins, Linda G Zachariassen, Pernille Sønderby Tuelung, Jeffrey R McArthur, David J Adams, Anders S Kristensen, Baldomero Olivera, Rocio K Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard
{"title":"一个以前未被识别的大锥虫毒素超家族包括感觉神经元钙通道Cav2.3抑制剂。","authors":"Celeste M Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D Kjelgaard, Maren Watkins, Linda G Zachariassen, Pernille Sønderby Tuelung, Jeffrey R McArthur, David J Adams, Anders S Kristensen, Baldomero Olivera, Rocio K Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard","doi":"10.1371/journal.pbio.3002217","DOIUrl":null,"url":null,"abstract":"<p><p>Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.</p>","PeriodicalId":20240,"journal":{"name":"PLoS Biology","volume":null,"pages":null},"PeriodicalIF":7.8000,"publicationDate":"2023-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10437998/pdf/","citationCount":"0","resultStr":"{\"title\":\"A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.\",\"authors\":\"Celeste M Hackney, Paula Flórez Salcedo, Emilie Mueller, Thomas Lund Koch, Lau D Kjelgaard, Maren Watkins, Linda G Zachariassen, Pernille Sønderby Tuelung, Jeffrey R McArthur, David J Adams, Anders S Kristensen, Baldomero Olivera, Rocio K Finol-Urdaneta, Helena Safavi-Hemami, Jens Preben Morth, Lars Ellgaard\",\"doi\":\"10.1371/journal.pbio.3002217\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. 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A previously unrecognized superfamily of macro-conotoxins includes an inhibitor of the sensory neuron calcium channel Cav2.3.
Animal venom peptides represent valuable compounds for biomedical exploration. The venoms of marine cone snails constitute a particularly rich source of peptide toxins, known as conotoxins. Here, we identify the sequence of an unusually large conotoxin, Mu8.1, which defines a new class of conotoxins evolutionarily related to the well-known con-ikot-ikots and 2 additional conotoxin classes not previously described. The crystal structure of recombinant Mu8.1 displays a saposin-like fold and shows structural similarity with con-ikot-ikot. Functional studies demonstrate that Mu8.1 curtails calcium influx in defined classes of murine somatosensory dorsal root ganglion (DRG) neurons. When tested on a variety of recombinantly expressed voltage-gated ion channels, Mu8.1 displayed the highest potency against the R-type (Cav2.3) calcium channel. Ca2+ signals from Mu8.1-sensitive DRG neurons were also inhibited by SNX-482, a known spider peptide modulator of Cav2.3 and voltage-gated K+ (Kv4) channels. Our findings highlight the potential of Mu8.1 as a molecular tool to identify and study neuronal subclasses expressing Cav2.3. Importantly, this multidisciplinary study showcases the potential of uncovering novel structures and bioactivities within the largely unexplored group of macro-conotoxins.
期刊介绍:
PLOS Biology is an open-access, peer-reviewed general biology journal published by PLOS, a nonprofit organization of scientists and physicians dedicated to making the world's scientific and medical literature freely accessible. The journal publishes new articles online weekly, with issues compiled and published monthly.
ISSN Numbers:
eISSN: 1545-7885
ISSN: 1544-9173