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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Lichtenegger, M; Stockner, T; Poteser, M; Schleifer, H; Platzer, D; Romanin, C; Groschner, K.
A novel homology model of TRPC3 reveals allosteric coupling between gate and selectivity filter.
Cell Calcium. 2013; 54(3):175-185
Doi: 10.1016/j.ceca.2013.05.010
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- Leading authors Med Uni Graz
- Groschner Klaus
- Lichtenegger Michaela
- Co-authors Med Uni Graz
- Platzer Dieter
- Poteser Michael
- Schleifer Hannes
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- Abstract:
- Utilizing a novel molecular model of TRPC3, based on the voltage-gated sodium channel from Arcobacter butzleri (Na(V)AB) as template, we performed structure-guided mutagenesis experiments to identify amino acid residues involved in divalent permeation and gating. Substituted cysteine accessibility screening within the predicted selectivity filter uncovered amino acids 629-631 as the narrowest part of the permeation pathway with an estimated pore diameter of < 5.8Å. E630 was found to govern not only divalent permeability but also sensitivity of the channel to block by ruthenium red. Mutations in a hydrophobic cluster at the cytosolic termini of transmembrane segment 6, corresponding to the S6 bundle crossing structure in Na(V)AB, distorted channel gating. Removal of a large hydrophobic residue (I667A or I667E) generated channels with approximately 60% constitutive activity, suggesting I667 as part of the dynamic structure occluding the permeation path. Destabilization of the gate was associated with reduced Ca2+ permeability, altered cysteine cross-linking in the selectivity filter and promoted channel block by ruthenium red. Collectively, we present a structural model of the TRPC3 permeation pathway and localize the channel's selectivity filter and the occluding gate. Moreover, we provide evidence for allosteric coupling between the gate and the selectivity filter in TRPC3.
- Find related publications in this database (using NLM MeSH Indexing)
- Allosteric Regulation -
- Amino Acid Sequence -
- Arcobacter - metabolism
- Calcium - metabolism
- Calcium Signaling - drug effects
- HEK293 Cells -
- Humans -
- Models, Molecular -
- Molecular Sequence Data -
- Mutagenesis, Site-Directed -
- Patch-Clamp Techniques -
- Protein Structure, Tertiary -
- Ruthenium Red - pharmacology
- Static Electricity -
- TRPC Cation Channels - chemistry
- Find related publications in this database (Keywords)
- TRPC3
- Homology modeling
- Selectivity
- Gating