Presentation Title
Structures of a sperm-specific solute carrier gated by voltage and cAMP
Presentation Abstract
The newly characterized sperm-specific Na+/H+ exchanger (sNHE) SLC9C1 stands out by its unique tripartite domain composition. It unites a canonical NHE transport domain (TD) with regulatory domains usually found in ion channels, namely a voltage-sensing domain (VSD) and a cyclic-nucleotide binding domain (CNBD). These domains endow the protein with a unique activation mechanism – the transport activity occurs only upon membrane hyperpolarization, with V1/2 modulated by cAMP. SLC9C1 is a mechanistic chimera and the first reported secondary-active transporter activated exclusively by membrane voltage, akin to CNBD ion channels. Our structures of the sea urchin homolog SpSLC9C1 in absence and presence of ligands reveal the overall domain arrangement and new structural coupling elements, which mediate the interactions between the three functional units (TD, VSD and CNBD). Further, cAMP, and not cGMP, induces significant mobility in the cytoplasmic domain. The structures allow us to propose a gating model, where at rest the TD is locked in the inward-facing conformation by the interactions with the cytoplasmic domain. Movements in the voltage sensor upon membrane hyperpolarization presumably displace the newly characterized coupling helices, and indirectly cause the release of the TD from its locked state. We further propose that modulation by cAMP occurs via disruption of the inter-protomer interactions within the cytoplasmic domain, which facilitates the downward S4 movement at resting membrane potential.
About Valeriia
Valeriia obtained her doctoral degree with the group of Raimund Dutzler of the University of Zurich, where she trained in biochemistry and structural biology of membrane proteins. Afterwards, she joined the group of Cristina Paulino of the University of Groningen, where she gained experience in single particle cryo-EM. She is currently a postdoc at the group of Petri Kursula of the University of Bergen and works with myelin-specific membrane proteins.
