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The voltage-dependent potassium (Kv) channel Kv1.3 regulates leukocyte proliferation, activation, and apoptosis, and altered expression of this channel is linked to autoimmune diseases. Thus, the fine-tuning of Kv1.3 function is crucial for the immune system response. The Kv1.3 accessory protein, potassium voltage-gated channel subfamily E (KCNE) subunit 4, acts as a dominant negative regulatory subunit to both enhance inactivation and induce intracellular retention of Kv1.3. Mutations in KCNE4 also cause immune system dysfunction. Although the formation of Kv1.3-KCNE4 complexes has profound consequences for leukocyte physiology, the molecular determinants involved in the Kv1.3-KCNE4 association are unknown. We now show that KCNE4 associates with Kv1.3 via a tetraleucine motif situated within the carboxy-terminal domain of this accessory protein. This motif would function as an interaction platform, in which Kv1.3 and Ca/calmodulin compete for the KCNE4 interaction. Finally, we propose a structural model of the Kv1.3-KCNE4 complex. Our experimental data and the in silico structure suggest that the KCNE4 interaction hides a forward-trafficking motif within Kv1.3 in addition to adding a strong endoplasmic reticulum retention signature to the Kv1.3-KCNE4 complex. Thus, the oligomeric composition of the Kv1.3 channelosome fine-tunes the precise balance between anterograde and intracellular retention elements that control the cell surface expression of Kv1.3 and immune system physiology.-Solé, L., Roig, S. R., Sastre, D., Vallejo-Gracia, A., Serrano-Albarrás, A., Ferrer-Montiel, A., Fernández-Ballester, G., Tamkun, M. M., Felipe, A. The calmodulin-binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3.
This article was published in the following journal.
Name: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
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A family of RNA-BINDING PROTEINS that contain an RNA RECOGNITION MOTIF and two ribonucleoprotein (RNP) domains which bind RNA, in addition to other domains that allow for high affinity binding, sequence specificity, and protein interactions. Examples of RNA recognition motif proteins include HETEROGENEOUS NUCLEAR RIBONUCLEARPROTEINS (hnRNP) and EMBRYONIC LETHAL ABNORMAL-VISION (ELAV) proteins.
Proteins which bind calmodulin. They are found in many tissues and have a variety of functions including F-actin cross-linking properties, inhibition of cyclic nucleotide phosphodiesterase and calcium and magnesium ATPases.
A helix-turn-helix motif characterized by three alpha-helices and four-stranded beta-sheets arranged in the order alpha1-beta1-beta2-alpha2-alpha3-beta3-beta4. The third alpha-helix contacts the major groove of DNA. The ETS motif and the flanking amino acid sequences of Ets proteins influence the binding affinity, and the alteration of a single amino acid in the Ets domain can change its DNA binding specificity.
An RNA-binding motif characterized by an alpha-beta-beta-beta-alpha fold that binds DOUBLE-STRANDED RNA. It occurs in many eukaryotic proteins as well as in bacterial and viral proteins.
An approximately 80 amino acid RNA binding motif that consists of four anti-parallel surface beta sheets and two alpha helices arranged in a beta-alpha-beta-beta-alpha-beta configuration. One of the surface beta sheets interacts with two or three specific RNA bases. Interactions between additional sequences and the RNA, as well as within the RNA recognition motif increase the affinity and specificity of the protein-RNA interaction.
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