Biophysical Society Conference | Tahoe 2023

Proton Reactions: From Basic Science to Biomedical Applications

Wednesday Speaker Abstracts

BIOPHYSICAL PROPERTIES OF NEWLY FOUND VOLTAGE-GATED PROTON CHANNELS Gustavo Chaves 1 ; Christophe Jardin 1 ; Christian Derst 1 ; Boris Musset 1 ; 1 Paracelsus Medical University, Center of Physiology, Pathophysiology and Biophysics, Nuremberg, Germany Voltage-gated proton channels (H V ) are found in various organisms, ranging from unicellular organisms to complex vertebrates. The H V family is small compared to other voltage-activated ion channels, with most species encoding H V from a single gene. However, we have recently reported the expansion of the H V family, where the first paralogs of the typical H V 1 within a single species have been found 1,2 . These new channels retain typical biophysical characteristics, such as perfect proton selectivity, pH- and voltage-regulated proton conductance, and inhibition by divalent cations. Nevertheless, subtle differences in their functioning have been detected, which may be related to small but significant structural components. For example, some modern insect H V s exhibit a natural variation in the selectivity filter and activate negatively to the Nernst potential for protons, allowing proton influx to the cell 3 . In contrast, molluscan H V 1 channels behave like typical proton extruder channels from other species, while their H V 2 paralogs conduct protons inwardly, similar to dinoflagellate H V s driving bioluminescent flashes .Other molluscan H V s show remarkable structural differences to H V 1 or H V 2. For instance, H V 4 channels from bivalvian molluscs, together with some fungal H V , are the smallest H V channels found in nature and exhibit a natural variation to a Lys (K3) in the third gating charge carrier (R3) of their voltage-sensor motif (VSM). In contrast, the H V 3 family found in molluscs contains the largest H V channels found to date, harbouring an atypical LPWRxxR VSM that results in a disrupted channel that leaks protons in the closed state and shows weak voltage-dependence of gating. Intriguingly, similar effects were observed when the physicochemical properties of the hydrophobic gasket of human H V 1 were altered. The characterization of the biophysical properties of these novel channels will help us to identify the structural determinants that spread the functional diversity the H V molecules.References:1. Chaves G, Jardin C, Franzen A, Mahorivska I, Musset B, Derst C. Proton channels in molluscs: A new bivalvian-specific minimal HV 4 channel. FEBS J. 2023 Feb 14. doi: 10.1111/febs.16751. Epub ahead of print. PMID: 36788452.2. Chaves G, Ayuyan AG, Cherny VV, Morgan D, Franzen A, Fieber L, Nausch L, Derst C, Mahorivska I, Jardin C, DeCoursey TE, Musset B. Unexpected expansion of the voltage-gated proton channel family. FEBS J. 2023 Feb;290(4):1008-1026. doi: 10.1111/febs.16617. Epub 2022 Sep 20. PMID: 36062330.3. Chaves G, Derst C, Jardin C, Franzen A, Musset B. Voltage-gated proton channels in polyneopteran insects. FEBS Open Bio. 2022 Feb;12(2):523-537. doi: 10.1002/2211-5463.13361. Epub 2022 Jan 19. PMID: 34986517; PMCID: PMC8804609.

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