Structural plasticity and dynamic selectivity of acid-sensing ion channel–spider toxin complexes

Abstract

Acid sensing ion channels (ASICs) are voltage-independent, amiloride-sensitive channels implicated in diverse physiological processes ranging from nociception to taste. Despite the importance of ASICs in physiology, we know little about the mechanism of channel activation. Here we show that psalmotoxin activates non- and sodium-selective currents in chicken ASIC1a at pH 7.25 and 5.5, respectively. Crystal structures of ASIC1a – psalmotoxin complexes map the toxin binding site to the extracellular domain and illuminate how toxin binding triggers an expansion of the extracellular vestibule and stabilization of the open channel pore. At pH 7.25 the pore is ~10 Å in diameter whereas at pH 5.5 the pore is largely hydrophobic and elliptical in cross section with dimensions of ~5 by ~7 Å, consistent with a barrier mechanism for ion selectivity. These studies define mechanisms for activation of ASICs, illuminate the basis for dynamic ion selectivity and provide the blueprints for new therapeutic agents.

Combination of Ambiguous and Unambiguous Data in the Restraint-driven Docking of Flexible Peptides with HADDOCK: The Binding of the Spider Toxin PcTx1 to the Acid Sensing Ion Channel (ASIC) 1a

“…25 Subsequently, the co-crystal structure of PcTx1 in complex with chicken ASIC1 (cASIC1) was published. 33,34 This confirmed the predicted location of the binding site and the fact that the structure of the binding site was largely unaffected by the presence of the peptide. Indeed, the root mean squared deviation (RMSD) between all residues within 10 Å of the peptide in the complex and those in the apo structure was < 1 Å.…”

“…For this system, both the apo-structure of the channel and the structure of the peptide-channel complex have been solved crystallographically. 33,34,39 In addition, an ensemble of high-quality NMR structures for the peptide is available. 25 The PcTx1-ASIC1 system has also been the focus of previous docking studies performed before the cocrystal structure was available.…”

“…These residues were modelled based on the equivalent section from an alternative PcTx1-cASIC1 crystal structure (PDB 4FZ1). 33 These residues are not involved in the binding of PcTx1. For the C X P N and C X P N20 docking experiments the same channel structure as in the C X P X experiments was used while the peptide structure was taken from the PcTx1 NMR structure PDB 2KNI.…”

Asymmetric perturbations of signalling oligomers

“…Acid-sensing ion channels (ASICs) are symmetric homotrimers as shown via XRC of ASIC1A-psalmotoxin complexes (Baconguis and Gouaux, 2012). In contrast, XRC at low pH demonstrated rearranged TM helices and asymmetric opening of a Na + -selective channel.…”

An efficient transcriptome analysis pipeline to accelerate venom peptide discovery and characterisation

“…Toxins have also been used to probe receptor-ligand interactions at their respective molecular targets. For example, the crystal structure of ASIC1a bound to psalmotoxin-1 (Baconguis and Gouaux, 2012;Dawson et al, 2012) isolated from the spider Araneae theraphosidae (Escoubas et al, 2000) was used to map the toxin-binding domain and understand activation mechanisms of ASICs (Baconguis and Gouaux, 2012). The co-crystallisation of ASIC1a with MitTx, a pain causing Texas coral snake toxin revealed the open state conformation of the channel (Baconguis et al, 2014).…”