PI4K2A is important in lysosomal quality control. It is the first essential enzyme of the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway for rapid lysosomal repair.[13] Upon lysosomal membrane damage, PI4K2A is strongly recruited to lysosomes, leading to robust lysosomal PI4P production. Such lysosomal PI4K2A/PI4P signaling drives rapid lysosomal repair through extensive membrane contacts between the endoplasmic reticulum (ER) and damaged lysosomes as well as multiple ER-to-lysosomal lipid transfer processes.
Pi4k2a gene trap mouse show pre-mature aging and neurodegeneration, with increased lipofuscin accumulation.[14] PI4K2A-deleted patients have complex and severe developmental problems along with neurodegeneration.[15]
Cartoon representation of the kinase domain of the phosphatidylinositol 4-kinase 2-alpha. N-lobe is colored in gold, C-lobe in aquamarine, ATP in the active site between the lobes in the stick representation. PDB code: 4PLA.[19]
PI4K2A is composed of a
proline-rich N-terminal region and a
kinase domain located C-terminally. The
proline-rich N-terminal region contains physiologically important binding sites for a
ubiquitin ligase Itch [20] and
clathrin adaptor complex 3,[21] but is likely disordered and dispensable for the kinase activity.[22] The
kinase domain can be divided into N-terminal and C-terminal lobes with the
ATP binding groove and putative
phosphatidylinositol binding pocket in between. The C-lobe of the
kinase domain contains an additional lateral hydrophobic pocket with no distinct function assigned yet.[19][23]
^Wu B, Kitagawa K, Zhang NY, Liu B, Inagaki C (December 2004). "Pathophysiological concentrations of amyloid beta proteins directly inhibit rat brain and recombinant human type II phosphatidylinositol 4-kinase activity". Journal of Neurochemistry. 91 (5): 1164–1170.
doi:
10.1111/j.1471-4159.2004.02805.x.
PMID15569259.
S2CID36690417.
Balla A, Balla T (July 2006). "Phosphatidylinositol 4-kinases: old enzymes with emerging functions". Trends in Cell Biology. 16 (7): 351–361.
doi:
10.1016/j.tcb.2006.05.003.
PMID16793271.
Minogue S, Waugh MG (2012). "The Phosphatidylinositol 4-Kinases: Don't Call it a Comeback". Phosphoinositides I: Enzymes of Synthesis and Degradation. Subcellular Biochemistry. Vol. 58. pp. 1–24.
doi:
10.1007/978-94-007-3012-0_1.
ISBN978-94-007-3011-3.
PMID22403072.