Volume regulated anion channels (VRACs) are important constituents of the cellular response against swelling in a process termed regulatory volume decrease. VRACS are formed by members of the LRRC8 family, which are restricted to chordates and which contain five closely related paralogs in humans (LRRC8A-E). In cells, LRRC8 proteins assemble as heteromeric channels all containing the obligatory A subunit and at least one additional B-E subunit that determines the selectivity of the channels. Whereas channels composed of A and C subunits are selective for small anions, channels containing the D and E subunits show a broader subunit selectivity, which also allows permeation of amino acids and osmolytes. These channels are also the primary uptake route for chemotherapeutics used in cancer therapy such as cisplatin and carboplatin.
By determining the structure of a homomeric channel composed of the obligatory LRRC8A subunit, our recent work has revealed the general architecture of the family23. Although not found in a cellular environment, these homomeric channels oligomerize into hexamers and form functional channels although with compromised activation properties. The structure, which was determined by a hybrid approach combining data from cryo-electron microscopy and X-ray crystallography, shows features that are general for the family as demonstrated in a comparison with a structure of a heteromeric channel determined at low resolution, and it has revealed insight into the structural basis of its anion selectivity.
The focus of ongoing work is on the structural characterization of heteromeric channels with different substrate selectivity, and determining the activation mechanism by which the protein senses changes of the intracellular ionic strength and tranduces this information into pore gating. Our research on this protein family is supported by a grant of the Swiss National Science Foundation.
23 Deneka, D., Sawicka, M., Lam, A. K. M., Paulino, C. & Dutzler, R. Structure of a volume-regulated anion channel of the LRRC8 family. Nature 558, 254-259 (2018).