Isoform-specific N-linked glycosylation of voltage-gated sodium channel alpha-subunits alters beta-subunit binding sites

Authors:
Preprint
Publisher website
Google Scholar
Abstract
Highlights Three N-linked glycosylation sites conserved among all Nav channels Glycan modelling and molecular dynamics simulations highlight 3D landscape Unique Nav1.5 N-linked glycans may prevent binding to Ig-domains of β1 and β3 Unique Nav1.8 N-linked glycan may prevent binding to Ig-domains of β2 and β4 N-linked glycans likely contribute to supra-molecular clustering of Nav channels Voltage-gated sodium channel α-subunits (Nav1.1-1.9) initiate and propagate action potentials in neurons and myocytes. The Nav β-subunits (β1-4) have been shown to modulate α-subunit properties. Homo-oligomerization of β-subunits on neighboring or opposing plasma membranes has been suggested to facilitate cis or trans interactions, respectively. The interactions between several Nav channel isoforms and β-subunits have been determined using cryogenic electron microscopy (cryo-EM). Interestingly, the Nav cryo-EM structures reveal the presence of N-linked glycosylation sites. However, only the first glycan moieties are typically resolved at each site due to the flexibility of mature glycan trees. Thus, existing cryo-EM structures may risk de-emphasizing the structural implications of glycans on the Nav channels. Herein, molecular modelling and all-atom molecular dynamics simulations were applied to investigate the conformational landscape of N-linked glycans on Nav channel surfaces. The simulations revealed that negatively-charged sialic acid residues of two glycan sites may interact with voltage-sensing domains. Notably, two Nav1.5 isoform-specific glycans extensively cover the α-subunit region that, in other Nav channel α-subunit isoforms, corresponds to the binding site for the β1-(and likely β3-) subunit immunoglobulin (Ig) domain. Nav1.8 contains a unique N-linked glycosylation site that likely prevents its interaction with the β2 and β4-subunit Ig domain. These isoform-specific glycans may have evolved to facilitate specific functional interactions, for example by redirecting β-subunit Ig-domains outwards to permit cis or trans supra-clustering within specialized cellular compartments such as the cardiomyocyte perinexal space. Further experimental work is necessary to validate these predictions.

This publication has 103 references indexed in Scilit: