TMC4 receptor binding properties and interaction mechanisms of salty mushroom peptides

The transmembrane channel-like protein 4 (TMC4) has been identified as a receptor for anionic salty compounds. However, whether salty peptides can activate TMC4 remains unresolved, and the underlying interaction mechanism between these peptides and the receptor is also unclear. In this study, we analyzed the binding properties and interaction mechanisms of salty mushroom peptides with the TMC4 receptor. A spontaneous, enthalpy-driven specific binding reaction was observed, with TMC4 binding to 2 molecules of the salty peptide KSWDDFFTR and 4 molecules of the peptide RIEDNLVIIR. The intracellular amino acid residues in pocket 1 of the receptor primarily recognized KSWDDFFTR, whereas the extracellular amino acid residues in pocket 4 predominantly bound to RIEDNLVIIR. Notably, the TMC4 receptor can be activated by the salty peptides, and the receptor specifically recognized uncharged peptides. Insights into the interaction between salty peptides and TMC4 may pave the way for the development of novel food additives.