TRPM7 is a typical representative of ChaK subfamily. TRPM7 (Transient Receptor Potential melastatin 7) is a transmembrane protein with dual functions of cation channels and kinase activity. As a non-selective cation channel, it can mediate inflow of divalent cations such as Mg²⁺, Ca²⁺, Zn²⁺ and outflow of monovalent cations such as K+ after opening; as a silk / threonine kinase, it can phosphorylate substrates and itself And can play the role of epigenetic factors, participate in gene expression regulation and other processes. TRPM7 is expressed in all tissues of the body, and is involved in intracellular Mg²⁺ homeostasis, cell migration, and adhesion. The unique structure, wide range of functions, and abundant expression make TRPM7 a promising new target for the treatment of major diseases such as cerebral ischemia, cardiovascular disease, and cancer.

Expression and structural characteristics of TRPM7

In the human genome, the TRPM7 gene is located on chromosome 15 and consists of 39 exons, encoding a total of 1865 amino acids. TRPM7 is widely distributed in mammalian organs, and is the most highly expressed TRP channel in adult mouse organs, such as brain, heart, kidney, lung, intestine, and testis. Compared to other TRP channel members, TRPM7 is most abundantly expressed in the dorsal root ganglia. At different stages of mouse embryonic development, the expression level of TRPM7 also showed significant differences: it reached a peak at 18 days of embryonic development, and a peak of expression appeared again on the fourth day after birth, after which it could maintain its expression level until the mouse adult. TRPM7 channel is a kind of channel protein that crosses the cell membrane and exists in the form of heterotetramer. It is a six-time transmembrane structure (S1-S6) on the cell membrane, and the channel aperture is formed between S5 and S6; E1047 or Y1049 can affect the sensitivity of the channel to Ca²⁺. The N-terminus and the C-terminus are located in the cell membrane. The N-terminus is mainly the four TPM family homology domains (Melastatin Ho-mology Domain, MHD). coil domain (CC) and protein kinase domain. The TRP box is a highly conserved and proline-rich domain consisting of approximately 25 amino acid residues that interacts with PIP2 to jointly regulate the function of the TRP channel; addition of the CC domain can mediate the formation of TRPM7 subunits and Source tetramers can also affect the sensitivity of the channel part to the Mg · NTP complex; the protein kinase domain at the C-terminus is an atypical α-kinase structure, which can not only phosphorylate itself and its substrate, but also It is cleaved by activated caspase and enhances ion channel function without affecting autophosphorylation activity. The TPM7 kinase domain consists of 1580 to 1863 amino acid residues, of which the 1781 to 1799 amino acid sequence contains a conserved ATP binding motif; H1751, H1808, C1804, and C1810 can complex with Zn²⁺ to form a Zn²⁺ binding motif. Maintaining kinase stability is important; K1646, D1765, Q1767, and D1775 are required for kinase activity. In addition, 1553 to 1562 amino acid residues constitute serine/proline-rich tablets segment, from 1563 to 1670 amino acid residues constitute the dimerization region.

Figure 1. Protein structure of TRPM7.

Functions

The mammalian homolog TRPs of the Drosophila transient receptor potential (trp) protein are thought to be ion channels that mediate the entry of calcium into cells. TRP-PLIK is a protein that is both an ion channel and a kinase. As a channel, it conducts calcium and monovalent cations, depolarizes cells and increases intracellular calcium. As a kinase, it can phosphorylate itself and other substrates. Kinase activity is necessary for channel function, as shown by its dependence on intracellular ATP and kinase mutants.

TRPM7 and cancer

TRPM7 and cancer TRPM7 participates in the growth, proliferation, differentiation and migration of various cancer cells. For example, reducing the expression of TRPM7 can inhibit the proliferation and invasion of cancer cells such as bladder cancer and prostate cancer. Therefore, TRPM7 is also listed as a cancer One of the targets. In addition, because TRPM7 is uniquely permeable to Ca²⁺ and Mg²⁺, it also makes it closer to cancer. For example, the TR148 polymorphic point mutation T1482I aggravates the symptoms of hereditary muscular atrophy and paralytic dementia, and the risk of disease will increase when the ratio of Ca²⁺ and Mg²⁺ is increased.

References

1. Ryazanov AG; et al. Identification of a new class of protein kinases represented by eukaryotic elongation factor-2 kinase. Proceedings of the National Academy of Sciences of the United States of America. 1997, 94 (10): 4884-9.
2. Runnels LW; et al. The TRPM7 channel is inactivated by PIP(2) hydrolysis. Nat. Cell Biol. 2002,4 (5): 329-36.