TRPM7

Function

Bifunctional protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. The channel is highly permeable to divalent cations, specifically calcium (Ca2+), magnesium (Mg2+) and zinc (Zn2+) and mediates their influx (PubMed:11385574, PubMed:12887921, PubMed:15485879, PubMed:24316671, PubMed:35561741, PubMed:36027648). Controls a wide range of biological processes such as Ca2(+), Mg(2+) and Zn(2+) homeostasis, vesicular Zn(2+) release channel and intracellular Ca(2+) signaling, embryonic development, immune responses, cell motility, proliferation and differentiation (By similarity). The C-terminal alpha-kinase domain autophosphorylates cytoplasmic residues of TRPM7 (PubMed:18365021). In vivo, TRPM7 phosphorylates SMAD2, suggesting that TRPM7 kinase may play a role in activating SMAD signaling pathways. In vitro, TRPM7 kinase phosphorylates ANXA1 (annexin A1), myosin II isoforms and a variety of proteins with diverse cellular functions (PubMed:15485879, PubMed:18394644).

TRPM7 channel, cleaved form

The cleaved channel exhibits substantially higher current and potentiates Fas receptor signaling.

TRPM7 kinase, cleaved form

The C-terminal kinase domain can be cleaved from the channel segment in a cell-type-specific fashion. In immune cells, the TRPM7 kinase domain is clipped from the channel domain by caspases in response to Fas-receptor stimulation. The cleaved kinase fragments can translocate to the nucleus, and bind chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to ultimately phosphorylate specific Ser/Thr residues of histones known to be functionally important for cell differentiation and embryonic development.

Involvement in disease

Amyotrophic lateral sclerosis-parkinsonism/dementia complex 1

ALS-PDC1

A neurodegenerative disorder characterized by chronic, progressive and uniformly fatal amyotrophic lateral sclerosis and parkinsonism-dementia. Both diseases are known to occur in the same kindred, the same sibship and even the same individual.

None

Disease susceptibility is associated with variants affecting the gene represented in this entry.

TRPM7 variants have been identified as a potential cause of disease in patients suffering from seizures and muscle cramps due to magnesium deficiency and episodes of hypocalcemia.

Post-translational modifications

Palmitoylated; palmitoylation at Cys-1143, Cys-1144 and Cys-1146 promotes TRPM7 trafficking from the Golgi to the surface membrane.

Autophosphorylated; autophosphorylation of C-terminus regulates TRPM7 kinase activity towards its substrates.

The C-terminal kinase domain can be cleaved from the channel segment in a cell-type-specific fashion. TRPM7 is cleaved by caspase-8, dissociating the kinase from the ion-conducting pore. The cleaved kinase fragments (M7CKs) can translocate to the cell nucleus and binds chromatin-remodeling complex proteins in a Zn(2+)-dependent manner to ultimately phosphorylate specific Ser/Thr residues of histones.

Sequence Similarities

In the C-terminal section; belongs to the protein kinase superfamily. Alpha-type protein kinase family. ALPK subfamily.

In the N-terminal section; belongs to the transient receptor (TC 1.A.4) family. LTrpC subfamily. TRPM7 sub-subfamily.

Cellular localization

• Cell membrane
• Multi-pass membrane protein
• Cytoplasmic vesicle membrane
• Multi-pass membrane protein
• Localized largely in intracellular Zn(2+)-storage vesicles.
• TRPM7 kinase, cleaved form
• Nucleus

Alternative names

CHAK1, LTRPC7, TRPM7, Transient receptor potential cation channel subfamily M member 7, Channel-kinase 1, Long transient receptor potential channel 7, LTrpC-7, LTrpC7

Database links

swissprot:Q96QT4 omim:605692 entrezGene:54822

Other research areas

• Cardiovascular