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A human-specific, truncated ?7 nicotinic receptor subunit assembles with full-length ?7 and forms functional receptors with different stoichiometries.

ABSTRACT: The cholinergic ?7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric ?7 receptor, involved in learning and memory. In humans, exons 5-10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A Its product, dup?7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulation. We combined dup?7 expression on mammalian cells with patch clamp recordings to understand its functional role. Transfected cells expressed dup?7 protein, but they exhibited neither surface binding of the ?7 antagonist ?-bungarotoxin nor responses to acetylcholine (ACh) or to an allosteric agonist that binds to the conserved transmembrane region. To determine whether dup?7 assembles with ?7, we generated receptors comprising ?7 and dup?7 subunits, one of which was tagged with conductance substitutions that report subunit stoichiometry and monitored ACh-elicited channel openings in the presence of a positive allosteric ?7 modulator. We found that ?7 and dup?7 subunits co-assemble into functional heteromeric receptors, which require at least two ?7 subunits for channel opening, and that dup?7's presence in the pentameric arrangement does not affect the duration of the potentiated events compared with that of ?7. Using an ?7 subunit mutant, we found that activation of (?7)2(dup?7)3 receptors occurs through ACh binding at the ?7/?7 interfacial binding site. Our study contributes to the understanding of the modulation of ?7 function by the human specific, duplicated subunit, associated with human disorders.

SUBMITTER: Lasala M

PROVIDER: S-EPMC6036215 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries.

Lasala Matías M Corradi Jeremías J Bruzzone Ariana A Esandi María Del Carmen MDC Bouzat Cecilia C

The Journal of biological chemistry 20180521 27

The cholinergic α7 nicotinic receptor gene, CHRNA7, encodes a subunit that forms the homopentameric α7 receptor, involved in learning and memory. In humans, exons 5-10 in CHRNA7 are duplicated and fused to the FAM7A genetic element, giving rise to the hybrid gene CHRFAM7A Its product, dupα7, is a truncated subunit lacking part of the N-terminal extracellular ligand-binding domain and is associated with neurological disorders, including schizophrenia, and immunomodulat ...[more]

PMID: 29784875

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Project description:The persistence of high concentrations of beta-2-microglobulin (?2M) in the blood of patients with acute renal failure leads to the development of the dialysis-related amyloidosis. This disease manifests in the deposition of amyloid fibrils formed from the various forms of ?2M in the tissues and biological fluids of patients. In this paper, the amyloid fibrils formed from the full-length ?2M (?2m) and its variants that lack the 6 and 10 N-terminal amino acids of the protein polypeptide chain (?N6?2m and ?N10?2m, respectively) were probed by using the fluorescent dye thioflavin T (ThT). For this aim, the tested solutions were prepared via the equilibrium microdialysis approach. Spectroscopic analysis of the obtained samples allowed us to detect one binding mode (type) of ThT interaction with all the studied variants of ?2M amyloid fibrils with affinity ~10? M-1. This interaction can be explained by the dye molecules incorporation into the grooves that were formed by the amino acids side chains of amyloid protofibrils along the long axis of the fibrils. The decrease in the affinity and stoichiometry of the dye interaction with ?2M fibrils, as well as in the fluorescence quantum yield and lifetime of the bound dye upon the shortening of the protein amino acid sequence were shown. The observed differences in the ThT-?2M fibrils binding parameters and characteristics of the bound dye allowed to prove not only the difference of the ?N10?2m fibrils from other ?2M fibrils (that can be detected visually, for example, by transmission electron microscopy (TEM), but also the differences between ?2m and ?N6?2m fibrils (that can not be unequivocally confirmed by other approaches). These results prove an essential role of N-terminal amino acids of the protein in the formation of the ?2M amyloid fibrils. Information about amyloidogenic protein sequences can be claimed in the development of ways to inhibit ?2M fibrillogenesis for the treatment of dialysis-related amyloidosis.

Dataset Information

A human-specific, truncated ?7 nicotinic receptor subunit assembles with full-length ?7 and forms functional receptors with different stoichiometries.

Publications

A human-specific, truncated α7 nicotinic receptor subunit assembles with full-length α7 and forms functional receptors with different stoichiometries.

Similar Datasets

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