Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP-1

Fuente-Ortega, Erwin de la; Gravotta, Diego; Bay, Andrés E. Perez; Benedicto, Ignacio; Carvajal-González, José María; Lehmann, Guillermo L.; Lagos, Carlos F.; Rodríguez-Boulan, Enrique

doi:10.1091/mbc.e15-01-0047

Cited by 13 publications

(18 citation statements)

References 73 publications

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“…These conflicting results were reconciled by recent observations that the c-r hemicomplex associates with dileucine-based motifs, instead of b or l subunits. [12,44,49]. Similar to tyrosine-based motifs, the bipartite signal reported in our study represents another atypical AP-1 l subunit interacting signal.…”

Section: Discussionsupporting

confidence: 77%

“…3H). Canonical dileucine motif failed to induce EXP-2/ Kv2.1 enrichment in dendrites It has been reported that the dileucine-based sorting signals ([L/I][L/I]) mediate transmembrane proteins polarized targeting in a variety of cells [21,[41][42][43][44]. In cortical pyramidal cells, a dileucine motif in the C-ter-minus of Shal channels is necessary and sufficient for dendritic targeting of Kv4.2, Kv1.3 and Kv1.4.…”

Section: Dendritic Targeting Of Exp-2-eqmil Chimera Needs Its N-termimentioning

confidence: 99%

“…Bipartite signal participates in the KVS-4 interaction with UNC-101/AP-1 l AP-1 is a heterocomplex comprised of b, r, c and l subunits, these subunits are implicated in the interaction with cytosolic sorting signals of transmembrane cargo proteins [10,14,15,44,47]. Some cargo proteins bind to AP-1 c-r hemicomplexes via dileucine motifs [12,44,48,49], whereas other proteins have been reported to associate with AP-1 l subunits via their YxxΦ motifs [50,51].…”

Section: C-terminal Q 552 M 553 and N-terminal I 254 Residues Are Essmentioning

confidence: 99%

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A novel bipartite UNC‐101/AP‐1 μ1 binding signal mediates KVS‐4/Kv2.1 somatodendritic distribution in Caenorhabditis elegans

et al. 2015

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Potassium channels such as Kv2.1 are targeted to specific subcellular compartments to fulfill various functions. However, the mechanisms for their localization are poorly understood. Here, we show that KVS‐4/Kv2.1 somatodendritic localization in Caenorhabditis elegansDA9 neuron requires UNC‐101(AP‐1 μ subunit). We define a bipartite sorting signal within KVS‐4 consisting of a C‐terminal EQMIL and N‐terminal WNIIE motifs. The bipartite signal is sufficient to target nonpolarized transmembrane protein MIG‐13 into DA9 somatodendritic compartments. Furthermore, we found that AP‐1 interacts with the bipartite signal through UNC‐101/AP‐1 μ N‐terminal predicted Longin‐like domain. Our results provide new insight into the mechanisms of Kv2.1 post‐Golgi sorting and targeting.

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Section: Discussionsupporting

confidence: 77%

Section: Dendritic Targeting Of Exp-2-eqmil Chimera Needs Its N-termimentioning

confidence: 99%

Section: C-terminal Q 552 M 553 and N-terminal I 254 Residues Are Essmentioning

confidence: 99%

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A novel bipartite UNC‐101/AP‐1 μ1 binding signal mediates KVS‐4/Kv2.1 somatodendritic distribution in Caenorhabditis elegans

et al. 2015

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“…14,15 In contrast, [DE]xxxL[LI] signals are recognized by the s1/g, s2/a, and s3/d subunits of AP-1, AP-2, and AP-3, respectively. [16][17][18][19] Finally, FxNPxY signals are recognized by co-adaptors dab2, numb and autosomal recessive hypercholesterolemia (ARH) protein. 20 Both dab2 and numb directly interact with the a subunit of AP-2.…”

Section: Basolateral Sorting Signals and Their Recognition By Cytosolmentioning

confidence: 99%

Role of the epithelial cell-specific clathrin adaptor complex AP-1B in cell polarity

Fölsch¹

2015

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“…We identified a tetraleucine motif within the C-terminal domain of KCNE4 that mediates the association with Kv1.3. Interestingly, dileucine motifs promote endocytosis, protein-protein interactions, and basolateral trafficking (43)(44)(45)(46). Altering the KCNE4 tetraleucine motif, as well as the suppression of the ERRM, improved the peptide targeting to the plasma membrane.…”

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confidence: 99%

The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

et al. 2019

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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 Ca2+/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.—Sole, 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. FASEB J. 33, 8263–8279 (2019). http://www.fasebj.org

show abstract

Basolateral sorting of chloride channel 2 is mediated by interactions between a dileucine motif and the clathrin adaptor AP-1

Cited by 13 publications

References 73 publications

A novel bipartite UNC‐101/AP‐1 μ1 binding signal mediates KVS‐4/Kv2.1 somatodendritic distribution in Caenorhabditis elegans

A novel bipartite UNC‐101/AP‐1 μ1 binding signal mediates KVS‐4/Kv2.1 somatodendritic distribution in Caenorhabditis elegans

Role of the epithelial cell-specific clathrin adaptor complex AP-1B in cell polarity

The calmodulin‐binding tetraleucine motif of KCNE4 is responsible for association with Kv1.3

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