Structure of acid-sensing ion channel 1 at 1.9 A resolution and low pH. Nature

Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Nature (Impact Factor: 41.46). 10/2007; 449(7160):316-23. DOI: 10.1038/nature06163
Source: PubMed


Acid-sensing ion channels (ASICs) are voltage-independent, proton-activated receptors that belong to the epithelial sodium channel/degenerin family of ion channels and are implicated in perception of pain, ischaemic stroke, mechanosensation, learning and memory. Here we report the low-pH crystal structure of a chicken ASIC1 deletion mutant at 1.9 A resolution. Each subunit of the chalice-shaped homotrimer is composed of short amino and carboxy termini, two transmembrane helices, a bound chloride ion and a disulphide-rich, multidomain extracellular region enriched in acidic residues and carboxyl-carboxylate pairs within 3 A, suggesting that at least one carboxyl group bears a proton. Electrophysiological studies on aspartate-to-asparagine mutants confirm that these carboxyl-carboxylate pairs participate in proton sensing. Between the acidic residues and the transmembrane pore lies a disulphide-rich 'thumb' domain poised to couple the binding of protons to the opening of the ion channel, thus demonstrating that proton activation involves long-range conformational changes.

1 Follower
18 Reads
  • Source
    • "Abbreviations include CRD, TM, and conserved amino acid residues motifs. Crystal structure of ASIC1 is from the Protein Data Bases (see legend of Fig. 1 for database references) doi: 10.2210/PBD:ID 2qts (Jasti et al. 2007). (C) Alignment of conserved pore region in SCNN1/ASIC-like channels. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypotheses of origins and evolution of neurons and synapses are controversial, mostly due to limited comparative data. Here, we investigated the genome-wide distribution of the bilaterian "synaptic" and "neuronal" protein-coding genes in non-bilaterian basal metazoans (Ctenophora, Porifera, Placozoa, and Cnidaria). First, there are no recognized genes uniquely expressed in neurons across all metazoan lineages. None of the so-called pan-neuronal genes such as embryonic lethal abnormal vision (ELAV), Musashi, or Neuroglobin are expressed exclusively in neurons of the ctenophore Pleurobrachia. Second, our comparative analysis of about 200 genes encoding canonical presynaptic and postsynaptic proteins in bilaterians suggests that there are no true "pan-synaptic" genes or genes uniquely and specifically attributed to all classes of synapses. The majority of these genes encode receptive and secretory complexes in a broad spectrum of eukaryotes. Trichoplax (Placozoa) an organism without neurons and synapses has more orthologs of bilaterian synapse-related/neuron-related genes than do ctenophores-the group with well-developed neuronal and synaptic organization. Third, the majority of genes encoding ion channels and ionotropic receptors are broadly expressed in unicellular eukaryotes and non-neuronal tissues in metazoans. Therefore, they cannot be viewed as neuronal markers. Nevertheless, the co-expression of multiple types of ion channels and receptors does correlate with the presence of neural and synaptic organization. As an illustrative example, the ctenophore genomes encode a greater diversity of ion channels and ionotropic receptors compared with the genomes of the placozoan Trichoplax and the demosponge Amphimedon. Surprisingly, both placozoans and sponges have a similar number of orthologs of "synaptic" proteins as we identified in the genomes of two ctenophores. Ctenophores have a distinct synaptic organization compared with other animals. Our analysis of transcriptomes from 10 different ctenophores did not detect recognized orthologs of synthetic enzymes encoding several classical, low-molecular-weight (neuro)transmitters; glutamate signaling machinery is one of the few exceptions. Novel peptidergic signaling molecules were predicted for ctenophores, together with the diversity of putative receptors including SCNN1/amiloride-sensitive sodium channel-like channels, many of which could be examples of a lineage-specific expansion within this group. In summary, our analysis supports the hypothesis of independent evolution of neurons and, as corollary, a parallel evolution of synapses. We suggest that the formation of synaptic machinery might occur more than once over 600 million years of animal evolution.
    Integrative and Comparative Biology 10/2015; DOI:10.1093/icb/icv104 · 2.93 Impact Factor
  • Source
    • "ASICs are proton-gated cation channels with a trimeric subunit arrangement [2]. They are abundant in the central and peripheral nervous systems, where they are involved in mechanosensation [3], nociception [4], memory and learning [5], as well as neurodegenerative disorders, such as ischemic stroke, epilepsy and Parkinson's disease [6]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: ASIC and ENaC are co-expressed in various cell types, and there is evidence for a close association between them. Here, we used atomic force microscopy (AFM) to determine whether ASIC1a and ENaC subunits are able to form cross-clade hybrid ion channels. ASIC1a and ENaC could be co-isolated from detergent extracts of tsA 201 cells co-expressing the two subunits. Isolated proteins were incubated with antibodies against ENaC and Fab fragments against ASIC1a. AFM imaging revealed proteins that were decorated by both an antibody and a Fab fragment with an angle of ∼120° between them, indicating the formation of ASIC1a/ENaC heterotrimers. Copyright © 2015. Published by Elsevier Inc.
    Biochemical and Biophysical Research Communications 05/2015; 464(1). DOI:10.1016/j.bbrc.2015.05.091 · 2.30 Impact Factor
  • Source
    • "Alternatively, PIP 2 may serve as a proton-sensitive ligand . An atomic structure is known for ASIC [37], but the role of PIP 2 in channel activation requires further investigation. Perhaps one reason for a slow adaptation of a " lipid-gating " model for PIP 2 is the fact that the prototypical PIP 2 -gated channel K ir is active during the resting state of excitable cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid–ligand bind to a membrane protein in the plasma membrane, and what does it mean for a lipid to activate or regulate an ion channel? How does lipid binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular, ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.
    Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 01/2015; 1851(5). DOI:10.1016/j.bbalip.2015.01.011 · 5.16 Impact Factor
Show more

Similar Publications