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Incompatibility between a pair of residues from the pre-M1 linker and Cys-loop blocks surface expression of the glycine receptor.

ABSTRACT: Regulation of cell membrane excitability can be achieved either by modulating the functional properties of cell membrane-expressed single channels or by varying the number of expressed channels. Whereas the structural basis underlying single channel properties has been intensively studied, the structural basis contributing to surface expression is less well characterized. Here we demonstrate that homologous substitution of the pre-M1 linker from the ? subunit prevents surface expression of the ?1 glycine receptor chloride channel. By investigating a series of chimeras comprising ?1 and ? subunits, we hypothesized that this effect was due to incompatibility between a pair of positively charged residues, which lie in close proximity to each other in the tertiary structure, from the pre-M1 linker and Cys-loop. Abolishing either positive charge restored surface expression. We propose that incompatibility (electrostatic repulsion) between this pair of residues misfolds the glycine receptor, and in consequence, the protein is retained in the cytoplasm and prevented from surface expression by the quality control machinery. This hypothesis suggests a novel mechanism, i.e. residue incompatibility, for explaining the mutation-induced reduction in channel surface expression, often present in the cases of hereditary hyperekplexia.

SUBMITTER: Shan Q

PROVIDER: S-EPMC3293590 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Incompatibility between a pair of residues from the pre-M1 linker and Cys-loop blocks surface expression of the glycine receptor.

Shan Qiang Q Lynch Joseph W JW

The Journal of biological chemistry 20120120 10

Regulation of cell membrane excitability can be achieved either by modulating the functional properties of cell membrane-expressed single channels or by varying the number of expressed channels. Whereas the structural basis underlying single channel properties has been intensively studied, the structural basis contributing to surface expression is less well characterized. Here we demonstrate that homologous substitution of the pre-M1 linker from the β subunit prevents surface expression of the α ...[more]

PMID: 22267740

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Incompatibility between a pair of residues from the pre-M1 linker and Cys-loop blocks surface expression of the glycine receptor.

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Incompatibility between a pair of residues from the pre-M1 linker and Cys-loop blocks surface expression of the glycine receptor.

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