Calmodulin-dependent KCNE4 dimerization controls membrane targeting

Roig, Sara R. and Solé, Laura and Cassinelli, Silvia and Colomer-Molera, Magalí and Sastre, Daniel and Serrano-Novillo, Clara and Serrano-Albarrás, Antonio and Lillo, M. Pilar and Tamkun, Michael M. and Felipe, Antonio. (2021) Calmodulin-dependent KCNE4 dimerization controls membrane targeting. Scientific Reports, 11 (1). p. 14046.

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The voltage-dependent potassium channel Kv1.3 participates in the immune response. Kv1.3 is essential in different cellular functions, such as proliferation, activation and apoptosis. Because aberrant expression of Kv1.3 is linked to autoimmune diseases, fine-tuning its function is crucial for leukocyte physiology. Regulatory KCNE subunits are expressed in the immune system, and KCNE4 specifically tightly regulates Kv1.3. KCNE4 modulates Kv1.3 currents slowing activation, accelerating inactivation and retaining the channel at the endoplasmic reticulum (ER), thereby altering its membrane localization. In addition, KCNE4 genomic variants are associated with immune pathologies. Therefore, an in-depth knowledge of KCNE4 function is extremely relevant for understanding immune system physiology. We demonstrate that KCNE4 dimerizes, which is unique among KCNE regulatory peptide family members. Furthermore, the juxtamembrane tetraleucine carboxyl-terminal domain of KCNE4 is a structural platform in which Kv1.3, Ca; 2+; /calmodulin (CaM) and dimerizing KCNE4 compete for multiple interaction partners. CaM-dependent KCNE4 dimerization controls KCNE4 membrane targeting and modulates its interaction with Kv1.3. KCNE4, which is highly retained at the ER, contains an important ER retention motif near the tetraleucine motif. Upon escaping the ER in a CaM-dependent pattern, KCNE4 follows a COP-II-dependent forward trafficking mechanism. Therefore, CaM, an essential signaling molecule that controls the dimerization and membrane targeting of KCNE4, modulates the KCNE4-dependent regulation of Kv1.3, which in turn fine-tunes leukocyte physiology.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Imaging Core Facility (Biehlmaier)
UniBasel Contributors:Roig Merino, Sara Raquel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Nature Publishing Group
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:03 Mar 2022 15:00
Deposited On:03 Mar 2022 15:00

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