Architecture and rearrangements of a sperm-specific Na+/H+ exchanger

Sandipan Chowdhury; Kamalendu Pal

doi:10.21203/rs.3.rs-3396005/v1

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Architecture and rearrangements of a sperm-specific Na+/H+ exchanger

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Architecture and rearrangements of a sperm-specific Na+/H+ exchanger

Sandipan Chowdhury and Kamalendu Pal

Research Square

American Journal Experts

10/11/2023

DOI: 10.21203/rs.3.rs-3396005/v1

PMCID: PMC10602139

PMID: 37886505

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Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

The sperm-specific sodium hydrogen exchanger, SLC9C1, underlies hyperpolarization and cyclic nucleotide stimulated proton fluxes across sperm membranes and regulates their hyperactivated motility. SLC9C1 is the first known instance of an ion transporter that uses a canonical voltage-sensing domain (VSD) and an evolutionarily conserved cyclic nucleotide binding domain (CNBD) to influence the dynamics of its ion-exchange domain (ED). The structural organization of this ‘tripartite transporter’ and the mechanisms whereby it integrates physical (membrane voltage) and chemical (cyclic nucleotide) cues are unknown. In this study, we use single particle cryo-electron microscopy to determine structures of a metazoan SLC9C1 in different conformational states. We find that the three structural domains are uniquely organized around a distinct ring-shaped scaffold that we call the ‘allosteric ring domain’ or ARD. The ARD undergoes coupled proton-dependent rearrangements with the ED and acts as a ‘signaling hub’ enabling allosteric communication between the key functional modules of sp9C1. We demonstrate that binding of cAMP causes large conformational changes in the cytoplasmic domains and disrupts key ARD-linked interfaces. We propose that these structural changes rescue the transmembrane domains from an auto-inhibited state and facilitate their functional dynamics. Our study provides a structural framework to understand and further probe electrochemical linkage in SLC9C1.

Details

Title: Subtitle: Architecture and rearrangements of a sperm-specific Na+/H+ exchanger
Creators: Sandipan Chowdhury - University of Iowa
Kamalendu Pal - University of Iowa
Resource Type: Preprint
Publication Details: Research Square
DOI: 10.21203/rs.3.rs-3396005/v1
PMID: 37886505
PMCID: PMC10602139
Publisher: American Journal Experts
Language: English
Date posted: 10/11/2023
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984500081802771

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