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

机译：在远端TRPM4 N末端的共享CAM和S100A1结合表位

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摘要

The transient receptor potential channel of melastatin 4 (TRPM4) 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 (TRPs) 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 TRPs 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 TRPM4 N terminus. We have used chemically synthesized peptides of the TRPM4, 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 TRPM4 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 TRPM4 N terminus-binding epitopes. The data suggest that the molecular complexes of TRPM4/CaM and TRPM4/S100A1 would lead to the modulation of the channel functions.
机译：猕猴桃4（TRPM4）的瞬态受体电位通道属于一组涉及无数牢房信号传导级联的大离子受体。这种独特的成员在许多人类组织中普遍表达，特别是在心肌细胞中，在那里它在心血管过程中起重要作用。瞬态受体电位通道（TRP）通常由细胞内N-和C-Termini构成，其作为影响通道的变构调制的介质，导致通道功能的调节。 TRPS尾部含有一些特异性结合细胞内调节剂的保守表位。这里，我们鉴定位于TRPM4 N末端的非常远侧的钙调蛋白（凸轮）和S100钙结合蛋白A1（S100A1）的新结合位点。我们已经使用了TRPM4的化学合成肽，模拟结合表位，以及荧光方法确定和指定CAM-and S100A1结合位点。我们发现配体在TRPM4 N末端重叠结合表位，但两个配合物的相互作用机制可能不同。来自荧光法的数据支持的分子模型证实，复合物形成由存在于TRPM4 N末端结合表位的带正电荷（R139，R140，R144）和疏水（L134，L138，V143）残基介导。数据表明TRPM4 / CAM和TRPM4 / S100A1的分子复合物将导致通道功能的调制。

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