Calmodulin-dependent KCNE4 dimerization controls membrane targeting

Abstract 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...

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Autores principales:	Sara R. Roig, Laura Solé, Silvia Cassinelli, Magalí Colomer-Molera, Daniel Sastre, Clara Serrano-Novillo, Antonio Serrano-Albarrás, M. Pilar Lillo, Michael M. Tamkun, Antonio Felipe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cc3eae485f4147a8837d506335056aeb
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spelling	oai:doaj.org-article:cc3eae485f4147a8837d506335056aeb2021-12-02T16:24:49ZCalmodulin-dependent KCNE4 dimerization controls membrane targeting10.1038/s41598-021-93562-52045-2322https://doaj.org/article/cc3eae485f4147a8837d506335056aeb2021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93562-5https://doaj.org/toc/2045-2322Abstract 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, Ca2+/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.Sara R. RoigLaura SoléSilvia CassinelliMagalí Colomer-MoleraDaniel SastreClara Serrano-NovilloAntonio Serrano-AlbarrásM. Pilar LilloMichael M. TamkunAntonio FelipeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sara R. Roig Laura Solé Silvia Cassinelli Magalí Colomer-Molera Daniel Sastre Clara Serrano-Novillo Antonio Serrano-Albarrás M. Pilar Lillo Michael M. Tamkun Antonio Felipe Calmodulin-dependent KCNE4 dimerization controls membrane targeting
description	Abstract 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, Ca2+/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.
format	article
author	Sara R. Roig Laura Solé Silvia Cassinelli Magalí Colomer-Molera Daniel Sastre Clara Serrano-Novillo Antonio Serrano-Albarrás M. Pilar Lillo Michael M. Tamkun Antonio Felipe
author_facet	Sara R. Roig Laura Solé Silvia Cassinelli Magalí Colomer-Molera Daniel Sastre Clara Serrano-Novillo Antonio Serrano-Albarrás M. Pilar Lillo Michael M. Tamkun Antonio Felipe
author_sort	Sara R. Roig
title	Calmodulin-dependent KCNE4 dimerization controls membrane targeting
title_short	Calmodulin-dependent KCNE4 dimerization controls membrane targeting
title_full	Calmodulin-dependent KCNE4 dimerization controls membrane targeting
title_fullStr	Calmodulin-dependent KCNE4 dimerization controls membrane targeting
title_full_unstemmed	Calmodulin-dependent KCNE4 dimerization controls membrane targeting
title_sort	calmodulin-dependent kcne4 dimerization controls membrane targeting
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/cc3eae485f4147a8837d506335056aeb
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Calmodulin-dependent KCNE4 dimerization controls membrane targeting

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