Jardin Christophe, Derst Christian, Franzen Arne, Mahorivska Iryna, DeCoursey Thomas E, Musset Boris, Chaves Gustavo
Center of Physiology, Pathophysiology and Biophysics-Nuremberg, Paracelsus Medical University, 90419 Nuremberg, Germany.
Institut für Biologische Informationsprozesse, Molekular-und Zellphysiologie (IBI-1), Forschungszentrum Jülich, 52428 Jülich, Germany.
Biomolecules. 2025 Jan 21;15(2):156. doi: 10.3390/biom15020156.
Somatic mutations are common in cancer, with only a few driving the progression of the disease, while most are silent passengers. Some mutations may hinder or even reverse cancer progression. The voltage-gated proton channel (H1) plays a key role in cellular pH homeostasis and shows increased expression in several malignancies. Inhibiting H1 in cancer cells reduces invasion, migration, proton extrusion, and pH recovery, impacting tumor progression. Focusing on , the gene coding for the human voltage-gated proton channel (hH1), 197 mutations were identified from three databases: 134 missense mutations, 51 sense mutations, and 12 introducing stop codons. These mutations cluster in two hotspots: the central region of the N-terminus and the region coding for the S4 transmembrane domain, which contains the channel's voltage sensor. Five somatic mutations within the S4 segment (R205W, R208W, R208Q, G215E, and G215R) were selected for electrophysiological analysis and MD simulations. The findings reveal that while all mutants remain proton-selective, they all exhibit reduced effective charge displacement and proton conduction. The mutations differentially affect hH1 kinetics, with the most pronounced effects observed in the two Arg-to-Trp substitutions. Mutation of the first voltage-sensing arginine (R1) to tryptophan (R205W) causes proton leakage in the closed state, accelerates channel activation, and diminishes the voltage dependence of gating. Except for R205W, the mutations promote the deactivated channel configuration. Altogether, these data are consistent with impairment of hH1 function by mutations in the S4 transmembrane segment, potentially affecting pH homeostasis of tumor cells.
体细胞突变在癌症中很常见，只有少数突变驱动疾病进展，而大多数是沉默突变。一些突变可能会阻碍甚至逆转癌症进展。电压门控质子通道（H1）在细胞pH稳态中起关键作用，并且在几种恶性肿瘤中表达增加。抑制癌细胞中的H1会降低侵袭、迁移、质子外排和pH恢复，从而影响肿瘤进展。聚焦于编码人类电压门控质子通道（hH1）的基因，从三个数据库中鉴定出197个突变：134个错义突变、51个同义突变和12个引入终止密码子的突变。这些突变聚集在两个热点区域：N端的中心区域和编码S4跨膜结构域的区域，该结构域包含通道的电压感受器。选择S4片段内的五个体细胞突变（R205W、R208W、R208Q、G215E和G215R）进行电生理分析和分子动力学模拟。研究结果表明，虽然所有突变体仍具有质子选择性，但它们都表现出有效电荷位移和质子传导降低。这些突变对hH1动力学有不同影响，在两个精氨酸到色氨酸的取代中观察到最明显的影响。第一个电压感应精氨酸（R1）突变为色氨酸（R205W）会导致通道在关闭状态下质子泄漏，加速通道激活，并降低门控的电压依赖性。除R205W外，这些突变促进失活通道构象。总之，这些数据与S4跨膜片段中的突变损害hH1功能一致，可能影响肿瘤细胞的pH稳态。
