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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na⁺ channels.

ABSTRACT: Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH₂-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface membrane localization and biophysical properties of voltage-dependent Na⁺ channels Nav1.2 and Nav1.6, but not Nav1.1. To further investigate the regulatory role of PRRT2, we studied the structural features of this membrane protein with molecular dynamics simulations, and its structure-function relationships with Nav1.2 channels by biochemical and electrophysiological techniques. We found that the intramembrane COOH-terminal region maintains a stable conformation over time, with the first transmembrane domain forming a helix-loop-helix motif within the bilayer. The unstructured NH₂-terminal cytoplasmic region bound to the Nav1.2 better than the isolated COOH-terminal intramembrane domain, mimicking full-length PRRT2, while the COOH-terminal intramembrane domain was able to modulate Na⁺ current and channel biophysical properties, still maintaining the striking specificity for Nav1.2 versus Nav1.1. channels. The results identify PRRT2 as a dual-domain protein in which the NH₂-terminal cytoplasmic region acts as a binding antenna for Na⁺ channels, while the COOH-terminal membrane domain regulates channel exposure on the membrane and its biophysical properties.

SUBMITTER: Franchi F

PROVIDER: S-EPMC10164911 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na<sup>+</sup> channels.

Franchi Francesca F Marte Antonella A Corradi Beatrice B Sterlini Bruno B Alberini Giulio G Romei Alessandra A De Fusco Antonio A Vogel Alexander A Maragliano Luca L Baldelli Pietro P Corradi Anna A Valente Pierluigi P Benfenati Fabio F

The Journal of biological chemistry 20230322 5

Proline-rich transmembrane protein 2 (PRRT2) is the single causative gene for pleiotropic paroxysmal syndromes, including epilepsy, kinesigenic dyskinesia, episodic ataxia, and migraine. PRRT2 is a neuron-specific type-2 membrane protein with a COOH-terminal intramembrane domain and a long proline-rich NH<sub>2</sub>-terminal cytoplasmic region. A large array of experimental data indicates that PRRT2 is a neuron stability gene that negatively controls intrinsic excitability by regulating surface ...[more]

PMID: 36958475

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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na⁺ channels.

Publications

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na<sup>+</sup> channels.

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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels.

Publications

The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na<sup>+</sup> channels.

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OmicsDI is part of the ELIXIR infrastructure

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The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na⁺ channels.