The Schistosoma mansoni tegumental allergen protein, SmTAL1: binding to an IQ-motif from a voltage-gated ion channel and effects of praziquantel

Charlotte M. Thomas, David Timson

Research output: Contribution to journalArticlepeer-review

Abstract

SmTAL1 is a calcium binding protein from the parasitic worm, Schistosoma mansoni. Structurally it is comprised of two domains – an N-terminal EF-hand domain and a C-terminal dynein light chain (DLC)-like domain. The protein has previously been shown to interact with the anti-schistosomal drug, praziquantel (PZQ). Here, we demonstrated that both EF-hands in the N-terminal domain are functional calcium ion binding sites. The second EF-hand appears to be more important in dictating affinity and mediating the conformational changes which occur on calcium ion binding. There is positive cooperativity between the four calcium ion binding sites in the dimeric form of SmTAL1. Both the EF-hand domain and the DLC-domain dimerise independently suggesting that both play a role in forming the SmTAL1 dimer. SmTAL1 binds non-cooperatively to PZQ and cooperatively to an IQ-motif from SmCav1B, a voltage-gated calcium channel. PZQ tends to strengthen this interaction, although the relationship is complex. These data suggest the hypothesis that SmTAL1 regulates at least one voltage-gated calcium channel and PZQ interferes with this process. This may be important in the molecular mechanism of this drug. It also suggests that compounds which bind SmTAL1, such as six from the Medicines for Malaria Box identified in this work, may represent possible leads for the discovery of novel antagonists.
Original languageEnglish
Article number102161
JournalCell Calcium
Volume86
DOIs
Publication statusPublished - 13 Jan 2020

Keywords

  • Calcium binding protein
  • EF-hand
  • IQ-motif
  • Praziquantel
  • Schistosomiasis
  • Voltage-gated calcium channel

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