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TitleScorpion α-toxin LqhαIT specifically interacts with a glycan at the pore domain of voltage-gated sodium channels.
Journal, issue, pagesStructure, Vol. 32, Issue 10, Page 1611-11620.e4, Year 2024
Publish dateOct 3, 2024
AuthorsSwastik Phulera / Callum J Dickson / Christopher J Schwalen / Maryam Khoshouei / Samantha J Cassell / Yishan Sun / Tara Condos / Jonathan Whicher / Wilhelm A Weihofen /
PubMed AbstractVoltage-gated sodium (Nav) channels sense membrane potential and drive cellular electrical activity. The deathstalker scorpion α-toxin LqhαIT exerts a strong action potential prolonging effect on ...Voltage-gated sodium (Nav) channels sense membrane potential and drive cellular electrical activity. The deathstalker scorpion α-toxin LqhαIT exerts a strong action potential prolonging effect on Nav channels. To elucidate the mechanism of action of LqhαIT, we determined a 3.9 Å cryoelectron microscopy (cryo-EM) structure of LqhαIT in complex with the Nav channel from Periplaneta americana (NavPas). We found that LqhαIT binds to voltage sensor domain 4 and traps it in an "S4 down" conformation. The functionally essential C-terminal epitope of LqhαIT forms an extensive interface with the glycan scaffold linked to Asn330 of NavPas that augments a small protein-protein interface between NavPas and LqhαIT. A combination of molecular dynamics simulations, structural comparisons, and prior mutagenesis experiments demonstrates the functional importance of this toxin-glycan interaction. These findings establish a structural basis for the specificity achieved by scorpion α-toxins and reveal the conserved glycan as an essential component of the toxin-binding epitope.
External linksStructure / PubMed:39181123
MethodsEM (single particle)
Resolution3.9 Å
Structure data

43438

8vqc

EMDB-43438, PDB-8vqc:
Structure of the voltage-gated sodium channel NavPas from American Cockroach Periplaneta Americana in complex with scorpion alpha-toxin LqhaIT
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • periplaneta americana (American cockroach)
  • leiurus quinquestriatus hebraeus (scorpion)
KeywordsMEMBRANE PROTEIN / NavPas / scorpion toxin / ion channel / voltage-gated sodium channel

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