Membrane Anchoring and Interaction between Transmembrane Domains are Crucial for K+ Channel Function

The small viral channel Kcv is a Kir-like K+ channel of only 94 amino acids. With this simple structure, the tetramer of Kcv represents the pore module of all complex K+ channels. To examine the structural contribution of the transmembrane domains (TMDs) to channel function, we performed Ala scannin...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-04, Vol.286 (13), p.11299-11306
Main Authors: Gebhardt, Manuela, Hoffgaard, Franziska, Hamacher, Kay, Kast, Stefan M., Moroni, Anna, Thiel, Gerhard
Format: Article
Language:English
Subjects:
Amino Acid Substitution
Animals
Genetic Complementation Test
Humans
Lipid Bilayers - chemistry
Lipid Bilayers - metabolism
Membrane Biophysics
Membrane Proteins
Models, Molecular
Molecular Biophysics
Mutation, Missense
Potassium Channels
Potassium Channels - chemistry
Potassium Channels - genetics
Potassium Channels - metabolism
Protein Structure
Protein Structure, Tertiary
Protein-Protein Interactions
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Structure-Activity Relationship
Viral Proteins - chemistry
Viral Proteins - genetics
Viral Proteins - metabolism
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Summary:The small viral channel Kcv is a Kir-like K+ channel of only 94 amino acids. With this simple structure, the tetramer of Kcv represents the pore module of all complex K+ channels. To examine the structural contribution of the transmembrane domains (TMDs) to channel function, we performed Ala scanning mutagenesis of the two domains and tested the functionality of the mutants in a yeast complementation assay. The data reveal, in combination with computational models, that the upper halves of both TMDs, which face toward the external medium, are rather rigid, whereas the inner parts are more flexible. The rigidity of the outer TMD is conferred by a number of essential aromatic amino acids that face the membrane and probably anchor this domain in the bilayer. The inner TMD is intimately connected with the rigid part of the outer TMD via π···π interactions between a pair of aromatic amino acids. This structural principle is conserved within the viral K+ channels and also present in Kir2.2, implying a general importance of this architecture for K+ channel function.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.211672