Project Details
Projekt
Functional specialization of transporting and non-transporting SLC26 proteins
Subject Area
Anatomy and Physiology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426950122
The functionally diverse SLC26 transporter family encompasses secondary-active anion exchangers, isoforms that mediate channel-like anion transport, and the voltage-driven motor protein prestin. Likewise, the substrate spectrum of SLC26 transporters – including chloride, bicarbonate, iodide, sulfate, and oxalate – differs between the ten mammalian isoforms. SLC26 transporters are involved in a variety of physiological processes, and their dysfunction is associated with severe human disease. Therefore, SLC26 transporters promise high potential as targets of novel therapeutic agents. Although a recent surge of experimental near-atomic structures from several SLC26 isoforms has substantially advanced our understanding of this protein family and provides a coherent picture of many structural commonalities, our current structural knowledge does not yet provide straightforward answers to the strikingly diverse functional properties across the transporter family. Thus, the structural mechanisms of SLC26 transporters – including the molecular underpinnings of the diversity of transport mechanisms and substrate selectivities – are unknown. Together with the availability of experimental structures, recent advances in deep-learning based protein-structure prediction now provide an excellent starting point to investigate the structure-dynamics-function relationships of this family of transporters. We will employ state-of-the-art high-performance computational biology techniques, including molecular dynamics (MD) simulations of SLC26 transporters under near-native conditions and Markov state modeling, to study selected SLC26 transporters with distinct transport characteristics. We will investigate the molecular mechanisms that underlie the different transport and coupling modes (e.g., anion exchange vs. channel-like ion transport), the unique electro-mechanical specialization of SLC26A5 (prestin), as well as the relevance of intersubunit cooperativity in SLC26 dimers. Informed by the obtained computational insights, we will experimentally interrogate SLC26 isoforms by electrophysiological and fluorometric transport assays, mutagenesis, and spectroscopic analysis of conformational dynamics to obtain validated mechanistic insights. Thereby, we will establish a comprehensive understanding of essential transport functions at atomic resolution and provide a basis for rational structure-guided drug development on SLC26 transporters.
DFG Programme
Research Units
