UC Berkeley

Cation-chloride-cotransporters (CCCs) play critical roles in cellular volume regulation, neural development and function, audition, regulation of blood pressure, and renal function. Disruption of CCCs has been implicated in pathophysiology including epilepsy, hearing loss, and genetic disorders. In this study, we present the structure of a CCC, the Mus musculus K+-Cl- cotransporter (KCC) KCC4, determined by cryo-EM. The structure, captured in an inward-open conformation, reveals the architecture of KCCs and offers mechanistic insights into the function and regulation of this important transporter family. Our findings provide a structural explanation for the varied substrate specificity and ion transport ratio among CCCs, identify binding sites for substrate K+ and Cl- ions, and demonstrate the importance of key coordinating residues for transporter activity. These insights have significant implications for developing novel drugs and treatments targeting CCCs.