title: Scorpion Potassium Channel-blocking Defensin Highlights a Functional Link with Neurotoxin.
abstract: The structural similarity between defensins and scorpion neurotoxins suggests that they might have evolved from a common ancestor. However, there is no direct experimental evidence demonstrating a functional link between scorpion neurotoxins and defensins. The scorpion defensin BmKDfsin4 from Mesobuthus martensiiKarsch contains 37 amino acid residues and a conserved cystine-stabilized α/β structural fold. The recombinant BmKDfsin4, a classical defensin, has been found to have inhibitory activity against Gram-positive bacteria such as Staphylococcus aureus, Bacillus subtilis, and Micrococcus luteusas well as methicillin-resistant Staphylococcus aureus Interestingly, electrophysiological experiments showed that BmKDfsin4,like scorpion potassium channel neurotoxins, could effectively inhibit Kv1.1, Kv1.2, and Kv1.3 channel currents, and its IC50value for the Kv1.3 channel was 510.2 nm Similar to the structure-function relationships of classical scorpion potassium channel-blocking toxins, basic residues (Lys-13 and Arg-19) of BmKDfsin4 play critical roles in peptide-Kv1.3 channel interactions. Furthermore, mutagenesis and electrophysiological experiments demonstrated that the channel extracellular pore region is the binding site of BmKDfsin4, indicating that BmKDfsin4 adopts the same mechanism for blocking potassium channel currents as classical scorpion toxins. Taken together, our work identifies scorpion BmKDfsin4 as the first invertebrate defensin to block potassium channels. These findings not only demonstrate that defensins from invertebrate animals are a novel type of potassium channel blockers but also provide evidence of a functional link between defensins and neurotoxins.
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Lanxia
authors.initials: L
authors.lastname: Meng
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and.
authors.forename: Zongyun
authors.initials: Z
authors.lastname: Chen
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and Center for BioDrug Research, Wuhan University, Wuhan 430072, China.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and Center for BioDrug Research, Wuhan University, Wuhan 430072, China zjcao@whu.edu.cn.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: From the State Key Laboratory of Virology, College of Life Sciences and Center for BioDrug Research, Wuhan University, Wuhan 430072, China ylwu@whu.edu.cn.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000254:growth & development; D023082:Defensins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D051662:Kv1.1 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051663:Kv1.2 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D016982:Micrococcus luteus / Q000187:drug effects / Q000254:growth & development; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009498:Neurotoxins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D012604:Scorpion Venoms / Q000096:biosynthesis / Q000737:chemistry*; D012605:Scorpions / Q000737:chemistry / Q000502:physiology; D016415:Sequence Alignment; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D023082:Defensins; D051663:Kv1.2 Potassium Channel; D051664:Kv1.3 Potassium Channel; D009498:Neurotoxins; D026902:Potassium Channel Blockers; D011994:Recombinant Proteins; D012604:Scorpion Venoms; D051662:Kv1.1 Potassium Channel
keywords: bacteria; defensin; neurotoxin; potassium channel; structure-function
references.citation: Curr Opin Immunol. 2002 Feb;14(1):96-102
references.pmid: 11790538
references.citation: J Biol Chem. 1996 Nov 22;271(47):29537-44
references.pmid: 8939880
references.citation: Cell Mol Life Sci. 2004 Jul;61(14):1751-63
references.pmid: 15241551
references.citation: Eur J Biochem. 1991 Feb 26;196(1):19-28
references.pmid: 1705886
references.citation: J Biol Chem. 1992 Jan 25;267(3):1640-7
references.pmid: 1730708
references.citation: Biochem Biophys Res Commun. 1993 Jul 15;194(1):17-22
references.pmid: 8333834
references.citation: J Biol Chem. 1993 Dec 15;268(35):26302-9
references.pmid: 8253752
references.citation: Biochemistry. 1994 Jun 7;33(22):6834-9
references.pmid: 8204618
references.citation: Proc Biol Sci. 1995 Aug 22;261(1361):217-21
references.pmid: 7568275
references.citation: Biophys J. 1997 Nov;73(5):2527-33
references.pmid: 9370446
references.citation: C R Seances Soc Biol Fil. 1998;192(3):445-62
references.pmid: 9759383
references.citation: Biochemistry. 1999 Apr 20;38(16):4922-30
references.pmid: 10213593
references.citation: Biochem J. 2005 Jan 1;385(Pt 1):95-104
references.pmid: 15588251
references.citation: J Pept Sci. 2004 Dec;10(12):714-8
references.pmid: 15635623
references.citation: Curr Protein Pept Sci. 2005 Feb;6(1):85-101
references.pmid: 15638771
references.citation: Trends Genet. 2005 Jun;21(6):330-2
references.pmid: 15922831
references.citation: Nature. 2005 Oct 13;437(7061):975-80
references.pmid: 16222292
references.citation: Cell Mol Life Sci. 2005 Oct;62(19-20):2257-69
references.pmid: 16143827
references.citation: J Biol Chem. 2006 Jan 6;281(1):313-23
references.pmid: 16246846
references.citation: Proteomics. 2006 Jun;6(12):3718-27
references.pmid: 16705749
references.citation: Arthropod Struct Dev. 2007 Jun;36(2):245-52
references.pmid: 18089103
references.citation: Proteins. 2008 Feb 15;70(3):844-54
references.pmid: 17729277
references.citation: J Biol Chem. 2008 Jul 4;283(27):19058-65
references.pmid: 18480054
references.citation: J Biol Chem. 2008 Aug 29;283(35):24177-84
references.pmid: 18559348
references.citation: Annu Rev Genomics Hum Genet. 2009;10:483-511
references.pmid: 19640225
references.citation: Science. 2010 May 28;328(5982):1168-72
references.pmid: 20508130
references.citation: J Proteome Res. 2010 Jun 4;9(6):3118-25
references.pmid: 20405930
references.citation: J Biol Chem. 2012 Apr 20;287(17):13813-21
references.pmid: 22354971
references.citation: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8495-500
references.pmid: 22586077
references.citation: J Biol Chem. 2013 May 3;288(18):12544-53
references.pmid: 23511633
references.citation: Curr Protein Pept Sci. 2013 Sep;14(6):515-31
references.pmid: 23968349
references.citation: Nat Commun. 2013;4:2602
references.pmid: 24129506
references.citation: Mol Biol Evol. 2014 Mar;31(3):546-59
references.pmid: 24425781
references.citation: Biochem Biophys Res Commun. 2014 Apr 25;447(1):70-6
references.pmid: 24704423
references.citation: J Proteomics. 2014 Jun 25;106:162-80
references.pmid: 24780724
references.citation: Toxins (Basel). 2015 Jan;7(1):34-42
references.pmid: 25568977
references.citation: Cell Mol Life Sci. 2015 Feb;72(4):845-53
references.pmid: 25238780
references.citation: Toxicon. 2015 Mar;95:52-61
references.pmid: 25553591
references.citation: Sci Rep. 2015;5:9881
references.pmid: 25955787
references.citation: J Biol Chem. 2015 Jun 19;290(25):15487-95
references.pmid: 25944908
references.citation: FASEB J. 2015 Oct;29(10):4324-33
references.pmid: 26148969
references.citation: Planta. 2002 Dec;216(2):193-202
references.pmid: 12447532