Shared CaM‐ and S100A1‐binding epitopes in the distal TRPM4 N terminus

The transient receptor potential channel of melastatin 4 ( TRPM 4) belongs to a group of large ion receptors that are involved in countless cell signalling cascades. This unique member is ubiquitously expressed in many human tissues, especially in cardiomyocytes, where it plays an important role in cardiovascular processes. Transient receptor potential channels ( TRP s) are usually constituted by intracellular N‐ and C‐ termini, which serve as mediators affecting allosteric modulation of channels, resulting in the regulation of the channel function. The TRP s tails contain a number of conserved epitopes that specifically bind the intracellular modulators. Here, we identify new binding sites for the calmodulin (CaM) and S100 calcium‐binding protein A1 (S100A1), located in the very distal part of the TRPM 4 N terminus. We have used chemically synthesized peptides of the TRPM 4, mimicking the binding epitopes, along with fluorescence methods to determine and specify CaM‐ and S100A1‐binding sites. We have found that the ligands binding epitopes at the TRPM 4 N terminus overlap, but the interacting mechanism of both complexes is probably different. The molecular models supported by data from the fluorescence method confirmed that the complexes formations are mediated by the positively charged (R139, R140, R144) and hydrophobic (L134, L138, V143) residues present at the TRPM 4 N terminus‐binding epitopes. The data suggest that the molecular complexes of TRPM 4/CaM and TRPM 4/S100A1 would lead to the modulation of the channel functions.