Departament de Bioquímica i Biomedicina Molecular, Molecular Physiology Laboratory, Institut de Biomedicina (IBUB), Universitat de Barcelona, Barcelona, Spain.
Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, USA.
FASEB J. 2019 Jul;33(7):8263-8279. doi: 10.1096/fj.201801164RR. Epub 2019 Apr 10.
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 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 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.
电压门控钾 (Kv) 通道 Kv1.3 调节白细胞的增殖、激活和凋亡，该通道表达的改变与自身免疫性疾病有关。因此，Kv1.3 功能的精细调节对于免疫系统的反应至关重要。Kv1.3 的辅助蛋白钾电压门控通道亚家族 E (KCNE) 亚基 4 作为一个显性负调节亚基，增强失活并诱导 Kv1.3 的细胞内保留。KCNE4 的突变也会导致免疫系统功能障碍。尽管 Kv1.3-KCNE4 复合物的形成对白细胞生理学有深远的影响，但涉及 Kv1.3-KCNE4 结合的分子决定因素尚不清楚。我们现在表明，KCNE4 与 Kv1.3 结合，该辅助蛋白的羧基末端结构域内有一个四亮氨酸基序。该基序将作为一个相互作用平台，其中 Kv1.3 和 Ca/钙调蛋白竞争与 KCNE4 的相互作用。最后，我们提出了 Kv1.3-KCNE4 复合物的结构模型。我们的实验数据和结构表明，除了向 Kv1.3-KCNE4 复合物添加强烈的内质网保留特征外，KCNE4 的相互作用隐藏了一个正向运输基序，该基序除了向 Kv1.3-KCNE4 复合物添加强烈的内质网保留特征外，还隐藏了一个正向运输基序。因此，Kv1.3 通道体的寡聚组成精细地调节了控制 Kv1.3 细胞表面表达和免疫系统生理学的正向运输和细胞内保留元件之间的精确平衡。- Solé，L.，Roig，S. R.，Sastre，D.，Vallejo-Gracia，A.，Serrano-Albarrás，A.，Ferrer-Montiel，A.，Fernández-Ballester，G.，Tamkun，M. M.，Felipe，A. KCNE4 的钙调蛋白结合四亮氨酸基序负责与 Kv1.3 结合。
