Abstract
The spatial localization of ion channels at the cell surface is crucial for their functional role. Many channels localize in lipid raft microdomains, which are enriched in cholesterol and sphingolipids. Caveolae, specific lipid rafts which concentrate caveolins, harbor signaling molecules and their targets becoming signaling platforms crucial in cell physiology. However, the molecular mechanisms involved in such spatial localization are under debate. Kv1.3 localizes in lipid rafts and participates in the immunological response. We sought to elucidate the mechanisms of Kv1.3 surface targeting, which govern leukocyte physiology. Kv1 channels share a putative caveolin-binding domain located at the intracellular N-terminal of the channel. This motif, lying close to the S1 transmembrane segment, is situated near the T1 tetramerization domain and the determinants involved in the Kvβ subunit association. The highly hydrophobic domain (FQRQVWLLF) interacts with caveolin 1 targeting Kv1.3 to caveolar rafts. However, subtle variations of this cluster, putative ancillary associations and different structural conformations can impair the caveolin recognition, thereby altering channel’s spatial localization. Our results identify a caveolin-binding domain in Kv1 channels and highlight the mechanisms that govern the regulation of channel surface localization during cellular processes.
Highlights
Localization, membrane dynamics suggest distinct membrane microdomain targeting[14,16,17,18]
Our study highlights the main mechanism of Kv1.3 channel membrane surface partitioning
Among Kv1 (Shaker) channels, only Kv1.3 and Kv1.5 targeted significantly to lipid rafts
Summary
Localization, membrane dynamics suggest distinct membrane microdomain targeting[14,16,17,18]. The Kv1.5-caveolin association is under debate[19,20] In this context, we have previously described the importance of protein interactions influencing Kv1.5 lipid raft targeting and postulate that several partners could compete to determine channel localization[18]. We study the influence of Cav on the lipid raft targeting of Kv1 channels by analyzing the function of a putative CBD motif conserved in the Shaker family. Both Kv1.3 and Kv1.5 target lipid rafts, but only Kv1.3 efficiently interacted with Cav via the CBD where this association is essential for the channel localization in these domains. The presence of a CBD near the T1 of Kv1.3 has important functional consequences for Kv1.3 channel physiology
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