PI4KB

This gene encodes a phosphatidylinositol 4-kinase which catalyzes phosphorylation of phosphatidylinositol at the D-4 position, yielding phosphatidylinositol 4-phosphate (PI4P). Besides the fact, that PI4P serves as a precursor for other important phosphoinositides, such as phosphatidylinositol 4,5-bisphosphate, PI4P is an essential molecule in the cellular signaling and trafficking especially in the Golgi apparatus and the trans Golgi network.

Phosphatidylinositol 4-kinases are evolutionary conserved among eukaryotes and include four human isoforms

• phosphatidylinositol 4-kinase alpha (PI4KA)
• phosphatidylinositol 4-kinase beta (PI4KB)
• phosphatidylinositol 4-kinase 2-alpha (PI4K2A)
• phosphatidylinositol 4-kinase 2-beta (PI4K2B)

Phosphatidylinositol 4-kinase beta (PI4KB) is a soluble protein shuttling between the cytoplasm and the nucleus,[8] and can be recruited to the membranes of the Golgi system via protein-protein interactions, e.g. with small GTP binding proteins Arf1[9] and Rab11,[10] or a Golgi adaptor protein ACBD3.[11][12] PI4KB can be phosphorylated by the protein kinase D,[13] which promotes the interaction with 14-3-3 proteins and stabilization of the protein in its active conformation.[14] In cytoplasm PI4KB regulates the trafficking from the Golgi system to the plasma membrane, nevertheless, its nuclear function remains to be determined.

A wide range of positive-sense single-stranded RNA viruses (e.g. picornaviruses) including many important human pathogens hijack human PI4KB kinase to generate specific PI4P-enriched organelles called membranous webs.[15] These organelles are then used as specific platforms for the effective viral replication within the host cell.

Furthermore, PI4KB homologue from the protozoan parasite Plasmodium falciparum has been identified as a target of imidopyrazines, an antimalarial compound class.[16]

PI4KB is composed of a proline-rich N-terminal region, a central helical domain, and a kinase domain located C-terminally. The N-terminal region contains a physiologically important binding site for a Golgi adaptor protein ACBD3, but is likely disordered and dispensable for the kinase activity. The central helical domain is responsible for the interaction with a small guanosine triphosphatase Rab11. The kinase domain can be divided into N-terminal and C-terminal lobes with the ATP binding groove and putative phosphatidylinositol binding pocket in a cleft between the lobes.[17] In addition, an ALPS motif has been identified in the extreme C-terminal region of PI4KB, which favors its association with unsaturated or loosely packed membranes regions.[18]

Cartoon representation of the helical and kinase domains of the phosphatidylinositol 4-kinase beta with a nucleoside analogue. Helical domain is colored in salmon, N-lobe of the kinase domain in gold, C-lobe in aquamarine, a specific inhibitor bound in the active site between the lobes in the stick representation. PDB code: 4WAG.