BF9

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Toxin BF9 is a Kunitz-type peptide, coming from snakes, with a dual functionality. The toxin is able to inhibit both serine proteases and potassium channels (more specifically the Kv1.3 channel).

Etymology and source[edit]

Venom basic protease inhibitor IX, also named BF9, is derived from the venom of the elapid snake Bungarus fasciatus. The ‘BF’ in the name originates from the snake's nomenclature. This Kunitz-type peptide is the first functionally characterized snake toxin that inhibits both proteases and potassium channels.[1]

Chemistry[edit]

The protein structure of BF9 has a length of 65 amino acid residues. Three of these residues are acidic and nine are basic. The basic residues of the protein are critical in forming the ‘functional dyad', which is a well-defined pair of amino acid residues that is essential for the protein’s function.[2] This ‘functional dyad’ is necessary to affect potassium channels.[3] The amino acid sequence of BF9 is the following:

‘KNRPTFCNLLPETGRCNALIPAFYYNSHLHKCQKFNYGGCGGNANNFKTIDECQRTCAAKYGRSS’.[4]

Target and mode of action[edit]

For the recognition of Kv1 potassium channels, the Kunitz-type toxins from snakes mainly use N-terminal residues.[5] To interact specifically with the Kv1.3 channels, based on sequence and structural comparative analysis with other Kunitz-type toxins, it is suggested that BF9 uses both its N-terminal and C-terminal residues.[1] The N-terminal residues involved are K1, R3, F6, L9, and L10. The C-terminal residues that are involved are R55, K60, and K63. These residues together form a molecular mechanism to interact with Kv1.3 channels. Due to this interaction, BF9 inhibits Kv1.3 channels with an IC50 value of 120.0 nM.[1]

Besides blocking Kv1.3 potassium channels, BF9 also acts as a serine protease inhibitor by interacting with specific proteases, such as alpha-chymotrypsin.[1] This inhibition is achieved by BF9 cleaving Asn17 at the P1 site of the target peptide. This P1 site of the target peptide interacts with the active site of a protease. BF9 is the first identified snake toxin capable of inhibiting both potassium channels and serine proteases.[6]

Therapeutic use[edit]

Kv1.3 channels are among others expressed in T-cells.[7] Therefore, if these channels are inhibited, the effector-memory T-cells are affected.[7]

The overexpression of Kv1.3 channels in T-cells can lead to autoimmune diseases,[7] and a higher level of factor XIa can lead to thrombosis.[8] Using its properties, BF9 can potentially be used as a treatment drug that targets the Kv1.3 channels and the XIa coregulation factor.[4]

References[edit]

  1. ^ a b c d Yang, Weishan; Feng, Jing; Wang, Bin; Cao, Zhijian; Li, Wenxin; Wu, Yingliang; Chen, Zongyun (2013-11-14). "BF9, the First Functionally Characterized Snake Toxin Peptide with Kunitz-Type Protease and Potassium Channel Inhibiting Properties: KUNITZ-TYPE PROTEASE AND POTASSIUM CHANNEL INHIBITOR FROM SNAKE". Journal of Biochemical and Molecular Toxicology. 28 (2): 76–83. doi:10.1002/jbt.21538. PMID 24243656. S2CID 1493475.
  2. ^ Mouhat, Stephanie; De Waard, Michel; Sabatier, Jean‐Marc (2004-12-20). "Contribution of the functional dyad of animal toxins acting on voltage‐gated Kv1‐type channels". Journal of Peptide Science. 11 (2): 65–68. doi:10.1002/psc.630. ISSN 1075-2617. PMID 15635666. S2CID 31444823.
  3. ^ Dauplais, Marc; Lecoq, Alain; Song, Jianxing; Cotton, Joël; Jamin, Nadège; Gilquin, Bernard; Roumestand, Christian; Vita, Claudio; de Medeiros, CleaneL.C.; Rowan, Edward G.; Harvey, Alan L.; Ménez, André (1997). "On the Convergent Evolution of Animal Toxins". Journal of Biological Chemistry. 272 (7): 4302–4309. doi:10.1074/jbc.272.7.4302. ISSN 0021-9258. PMID 9020148.
  4. ^ a b Ding, Li; Hao, Jinbo; Luo, Xudong; Zhu, Wen; Wu, Zheng; Qian, Yi; Hu, Fangfang; Liu, Tianli; Ruan, Xuzhi; Li, Shan; Li, Jian; Chen, Zongyun (2018-09-15). "The Kv1.3 channel-inhibitory toxin BF9 also displays anticoagulant activity via inhibition of factor XIa". Toxicon. 152: 9–15. doi:10.1016/j.toxicon.2018.07.014. ISSN 0041-0101. PMID 30012473. S2CID 51662942.
  5. ^ Wang, Fan C.; Bell, Natalie; Reid, Paul; Smith, Leonard A.; McIntosh, Paul; Robertson, Brian; Dolly, J. Oliver (2001-12-25). "Identification of residues in dendrotoxin K responsible for its discrimination between neuronal K+ channels containing Kv1.1 and 1.2 α subunits". European Journal of Biochemistry. 263 (1): 222–229. doi:10.1046/j.1432-1327.1999.00494.x. ISSN 0014-2956. PMID 10429207.
  6. ^ Ding, Li; Hao, Jinbo; Luo, Xudong; Chen, Zongyun (2018). "Engineering varied serine protease inhibitors by converting P1 site of BF9, a weakly active Kunitz-type animal toxin". International Journal of Biological Macromolecules. 120 (Pt A): 1190–1197. doi:10.1016/j.ijbiomac.2018.08.178. ISSN 0141-8130. PMID 30172807. S2CID 52146038.
  7. ^ a b c Beeton, Christine; Wulff, Heike; Standifer, Nathan E.; Azam, Philippe; Mullen, Katherine M.; Pennington, Michael W.; Kolski-Andreaco, Aaron; Wei, Eric; Grino, Alexandra; Counts, Debra R.; Wang, Ping H.; LeeHealey, Christine J.; S. Andrews, Brian; Sankaranarayanan, Ananthakrishnan; Homerick, Daniel (2006-11-14). "Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases". Proceedings of the National Academy of Sciences. 103 (46): 17414–17419. Bibcode:2006PNAS..10317414B. doi:10.1073/pnas.0605136103. ISSN 0027-8424. PMC 1859943. PMID 17088564.
  8. ^ Wu, Wenman; Li, Hongbo; Navaneetham, Duraiswamy; Reichenbach, Zachary W.; Tuma, Ronald F.; Walsh, Peter N. (2012-07-19). "The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis". Blood. 120 (3): 671–677. doi:10.1182/blood-2012-03-419523. ISSN 0006-4971. PMC 3401218. PMID 22674803.
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