JOURNAL ARTICLE
RESEARCH SUPPORT, NON-U.S. GOV'T
The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na + channels.
Journal of Biological Chemistry 2023 May
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.
Full text links
Trending Papers
Midline incisional hernia guidelines: the European Hernia Society.British Journal of Surgery 2023 September 20
Management of adult-onset Still's disease: evidence- and consensus-based recommendations by experts.Rheumatology 2023 September 6
AGA Clinical Practice Update on the Epidemiology, Evaluation, and Management of Exocrine Pancreatic Insufficiency: Expert Review.Gastroenterology 2023 September 21
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app
Read by QxMD is copyright © 2021 QxMD Software Inc. All rights reserved. By using this service, you agree to our terms of use and privacy policy.
You can now claim free CME credits for this literature searchClaim now
Get seemless 1-tap access through your institution/university
For the best experience, use the Read mobile app