Spinoxin
Spinoxin (SPX; α-KTx6.13) is a 34-residue peptide neurotoxin isolated from the venom of the Malaysian black scorpion Heterometrus spinifer. It is part of the α-KTx6 subfamily and exerts its effects by inhibiting voltage-gated potassium channels, specifically Kv1.2 and Kv1.3.[1]
Sources
[edit]Spinoxin is isolated from the venom of the Malaysian black scorpion H. spinifer, from which the toxin gets its name. Researchers first characterized it in 2003.[2]
Chemistry
[edit]Structure
[edit]Spinoxin is a peptide neurotoxin consisting of 34 amino acid residues. It has a molecular weight of 3.7 kDa.[3] All members of the α-KTx subfamily share a common cysteine-stabilized α/β motif (CSαβ).[1] In spinoxin the N-terminal contains the α-helix whereas the C-terminal contains the β-region/sheet, which is involved in the binding to the potassium-channel, resulting in blocking of the channel.[4] Four disulfide bridges connect these terminals stabilizing the small protein. The pattern of spinoxin disulfide bonding has been determined to be Cys3-Cys24, Cys9-Cys29, Cys13-Cys31, and Cys19-Cys34.[1] A 3D model of spinoxin can be viewed on this website.
| I R C S G S R D C Y S P C M K Q T G C P N A K C I N K S C K C Y G C-NH2 |
Family
[edit]Spinoxin belongs to the class of small proteins with knottin folds resulting from the four disulfide bonds. The superfamily spinoxin is part of is known as "scorpion toxin-like", and its family as "short-chain scorpion toxins".[5]
Homology
[edit]Spinoxin has 82% sequence homology with maurotoxin (MTX; α-KTx6.2).[6] Most short-chain scorpion toxins contain three disulfide bridges, whereas several toxins belonging to the α-KTx6 subfamily, including spinoxin and maurotoxin, possess a fourth disulfide bridge.
Target
[edit]Similar to maurotoxin, spinoxin is a member of the extensively studied α-KTx family of neurotoxins acting on voltage-gated potassium channels. However, little is known about spinoxin in particular. Spinoxin targets voltage-gated potassium channels Kv1.2 and Kv1.3, possibly by blocking the selectivity filter with its Lys residues.[1] It has no inhibitory effects on Kv1.1 channels.[1]
Mode of Action
[edit]It has been reported that the following three amino acid residues in particular are important for blocking of potassium channels: Lys23, Asn26, and Lys30. Furthermore, three out of the four disulfide bridges affect the intensity of the inhibition, specifically Cys3-Cys24, Cys9-Cys29, Cys13-Cys31. The Cys19-Cys34 bond does not seem to be required for Kv1.3 inhibition.[4]
Toxicity
[edit]Spinoxin can cause intense pain, visual disturbances and swelling of the affected area. However, it is not lethal to humans.[7]
References
[edit]- ^ a b c d e Peigneur, Steve; Yamaguchi, Yoko; Kawano, Chihiro; Nose, Takeru; Nirthanan, Selvanayagam; Gopalakrishnakone, Ponnampalam; Tytgat, Jan; Sato, Kazuki (2016). "Active Sites of Spinoxin, a Potassium Channel Scorpion Toxin, Elucidated by Systematic Alanine Scanning". Biochemistry. 55 (21): 2927–2935. doi:10.1021/acs.biochem.6b00139. hdl:10072/99824. ISSN 0006-2960. PMID 27159046.
- ^ Sugahara, Y.; Nirthanan, S.; Huys, I.; Kobayashi, K.; Kohno, T. (2003). "Synthesis and characterization of spinoxin, a novel peptide toxin from the Malaysian black scorpion". Peptide Science: 283–284.
- ^ a b "UniProtKB - P84094 (KAX6D_HETSP)". 2006-09-05.
- ^ a b Yamaguchi, Yoko; Peigneur, Steve; Liu, Junyi; Uemura, Shiho; Nose, Takeru; Nirthanan, Selvanayagam; Gopalakrishnakone, Ponnampalam; Tytgat, Jan; Sato, Kazuki (2016). "Role of individual disulfide bridges in the conformation and activity of spinoxin (α-KTx6.13), a potassium channel toxin from Heterometrus spinifer scorpion venom". Toxicon. 122: 31–38. doi:10.1016/j.toxicon.2016.09.013. ISSN 0041-0101. PMID 27660193.
- ^ "Superfamily". Superfamily database. 2013. Retrieved 2016-10-04.
- ^ Combelles, Cecil; Gracy, Jérôme; Heitz, Annie; Craik, David J.; Chiche, Laurent (2008). "Structure and folding of disulfide-rich miniproteins: Insights from molecular dynamics simulations and MM-PBSA free energy calculations". Proteins: Structure, Function, and Bioinformatics. 73 (1): 87–103. doi:10.1002/prot.22054. ISSN 0887-3585. PMID 18393393. S2CID 37469698.
- ^ Nirthanan, Selvanayagam; Joseph, Jeremiah S.; Gopalakrishnakone, Ponnampalam; Khoo, Hoon-Eng; Cheah, Li-Sam; Gwee, Matthew C.E. (2002). "Biochemical and pharmacological characterization of the venom of the black scorpion Heterometrus spinifer". Biochemical Pharmacology. 63 (1): 49–55. doi:10.1016/S0006-2952(01)00854-1. ISSN 0006-2952. PMID 11754873.