TPCN2
Description
The TPCN2 (two pore segment channel 2) is a protein-coding gene located on chromosome 11.
Two pore segment channel 2 (TPC2) is a protein which in humans is encoded by the TPCN2 gene. TPC2 is an ion channel, however, in contrast to other calcium and sodium channels which have four homologous domains, each containing 6 transmembrane segments (S1 to S6), TPCN1 only contains two domain (each containing segments S1 to S6).
== Structure == TPC2 is homologous to TPC1, the best characterized member of the TPC family. The structure of a TPC1 ortholog from Arabidopsis thaliana has been solved by two laboratories. The structures were solved using X-ray crystallography and contained the fold of a voltage-gated ion channel and EF hands.
== Filoviral infections == Genetic knockout and pharmacological inhibition experiments demonstrate that the two-pore channels, TPC1 and TPC2, are required for infection by Filoviruses Ebola and Marburg in mice.
TPCN2 is an intracellular channel that functions as both a calcium (Ca2+) and sodium (Na+) channel. It is primarily activated by nicotinic acid adenine dinucleotide phosphate (NAADP) for Ca2+ permeability and phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) for Na+ permeability. TPCN2 localizes to lysosomes and late endosomes, where it regulates organelle membrane excitability, membrane trafficking, and pH homeostasis. It is involved in a range of cellular processes, including mTOR-dependent nutrient sensing, skin pigmentation, and autophagy. TPCN2's ion selectivity is dependent on the activating agonist, and it can be activated by both NAADP and PI(3,5)P2 under specific ionic conditions. As a calcium channel, it increases lysosomal lumen pH, while as a sodium channel, it promotes lysosomal exocytosis. TPCN2 plays a crucial role in endolysosomal trafficking and the endolysosomal degradation pathway, potentially contributing to the homeostatic control of various macromolecules and cellular metabolites. It is also expressed in melanosomes of pigmented cells, where it acts as a Ca2+ channel and/or PI(3,5)P2-activated Na+ channel to acidify pH and inhibit tyrosinase activity, which is essential for melanogenesis and pigmentation. Unlike its voltage-dependent counterpart TPCN1, TPCN2 is voltage-independent and can be activated solely by PI(3,5)P2 binding. Other phosphoinositides, such as PI(4,5)P2, PI(3,4)P2, PI(3)P, and PI(5)P, do not have a significant effect on channel activation.
TPCN2 is also known as SHEP10, TPC2.
