Alternative Splicing Modulates Kv Channel Clustering through a Molecular `Ball and Chain' Mechanism

Ion channel clustering at the post-synaptic density (PSD) serves a fundamental role in action potential transmission. In voltage-activated potassium channels (Kv), this process is mediated by interaction of the C-terminal tail with scaffold proteins by a currently unclear mechanism. Here, we show that interaction between the prototypical Shaker Kv channel and the PSD-95 scaffold protein is entropy-controlled and modulated by the length of the intrinsically disordered channel tail. We further show that the Kv channel tail functions as entropic clock that times scaffold protein binding. Based on these observations, we propose a ‘ball and chain’ mechanism to explain C-terminal-based Kv channel binding to scaffold proteins, analogous to the classical N-type mechanism that describes channel fast inactivation. The physiological relevance of this mechanism is demonstrated by showing that alternative splicing in the Shaker Kv channel gene, producing channel variants with distinct C-terminal tail lengths, exhibit distinct scaffold protein-mediated channel cell surface expression and clustering patterns that correlate with differences in affinity of the variants to PSD-95. We suggest that modulating channel clustering by specific spatial-temporal variant targeting serves a fundamental role in nervous system development and tuning.