title: Alternative splicing modulates Kv channel clustering through a molecular ball and chain mechanism.
abstract: Ion channel clustering at the post-synaptic density serves a fundamental role in action potential generation and transmission. Here, we show that interaction between the Shaker Kv channel and the PSD-95 scaffold protein underlying channel clustering is modulated by the length of the intrinsically disordered C terminal channel tail. We further show that this tail functions as an entropic clock that times PSD-95 binding. We thus propose a 'ball and chain' mechanism to explain Kv channel binding to scaffold proteins, analogous to the mechanism describing channel fast inactivation. The physiological relevance of this mechanism is demonstrated in that alternative splicing of the Shaker channel gene to produce variants of distinct tail lengths resulted in differential channel cell surface expression levels and clustering metrics that correlate with differences in affinity of the variants for PSD-95. We suggest that modulating channel clustering by specific spatial-temporal spliced variant targeting serves a fundamental role in nervous system development and tuning.
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Nitzan
authors: N
authors: Zandany
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Shir
authors: S
authors: Marciano
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Elhanan
authors: E
authors: Magidovich
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Teddy
authors: T
authors: Frimerman
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Rinat
authors: R
authors: Yehezkel
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Tzilhav
authors: T
authors: Shem-Ad
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Limor
authors: L
authors: Lewin
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Uri
authors: U
authors: Abdu
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Irit
authors: I
authors: Orr
authors: Department of Life Sciences, Zlotowski Center for Neurosciences, Ben-Gurion University of the Negev, PO Box 653, Beer Sheva 84105, Israel.
authors: Ofer
authors: O
authors: Yifrach
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002850:Chromatography, Gel; D002942:Circular Dichroism; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D019277:Entropy; D018507:Gene Expression Regulation, Developmental; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D057907:Post-Synaptic Density / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism*; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D025521:Tumor Suppressor Proteins
chemical_list: D029721:Drosophila Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D051637:Shaker Superfamily of Potassium Channels; D025521:Tumor Suppressor Proteins; C070350:dlg1 protein, Drosophila