Protein Details: Two pore channel protein 2

Function

Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate); it is also a highly-selective Na(+) channel activated directly by PI(3;5)P2 (phosphatidylinositol 3;5-bisphosphate). Localizes to the lysosomal and late endosome membranes where it regulates organellar membrane excitability; membrane trafficking; and pH homeostasis. Is associated with a plethora of physiological processes; including mTOR-dependent nutrient sensing; skin pigmentation and autophagy. Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions; can be readily activated by both NAADP and PI(3;5)P2. As calcium channel; it increases the pH in the lysosomal lumen; as sodium channel; it promotes lysosomal exocytosis. Plays a crucial role in endolysosomal trafficking in the endolysosomal degradation pathway and is potentially involved in the homeostatic control of many macromolecules and cell metabolites (By similarity). Also expressed in melanosomes of pigmented cells where mediates a Ca(2+) channel and/or PI(3;5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit tyrosinase activity required for melanogenesis and pigmentation. Unlike the voltage-dependent TPCN1; TPCN2 is voltage independent and can be activated solely by PI(3;5)P2 binding. In contrast; PI(4;5)P2; PI(3;4)P2; PI(3)P and PI(5)P have no obvious effect on channel activation. (Microbial infection) During Ebola virus (EBOV) infection; controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm. (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2; as well as human coronavirus EMC (HCoV-EMC); by endocytosis.

Sequence

PDB Structures

Ligand Binding