Phosphatidylinositol transfer proteins: from closed for transport to open for exchange.

Since their purification from bovine brain phosphatidylinositol transfer proteins (PI-TP) have been subject to extensive studies mainly prompted by the hypothesis that these proteins play a key role in intracellular phosphatidylinositol (PI) transport and as a consequence, in PI-dependent signalling pathways (Helmkamp et al., 1974; Wirtz, 1997). To date, two isoforms of PI-TP have been identified: PI-TPa (270 amino acids) and PI-TPb (271 amino acids). Either isoform (Mr 32 kDa) is highly conserved (498% sequence identity) among mammalian species. Moreover, both proteins are highly homologous with a sequence identity of 77% (similarity of 94%) yet appear to have distinctly different cellular functions. In agreement with this the gene of human PI-TPa is localized to chromosome 17q13 and of PI-TPb to chromosome 22q12 (Ocaka et al., 2005). Both isoforms act as carriers of PI and phosphatidylcholine (PC) between membranes in vitro, yet PI-TPb can also transfer sphingomyelin (SPM) (Van Paridon et al., 1987b; De Vries et al., 1995). At this point it is still questionable whether these proteins actually transfer these phospholipids between membranes within cells or whether they interact directly with enzymes like PI 4-kinases and PI-specific phospholipase A2 thereby providing these enzymes with substrates (Cunningham et al., 1995; Snoek et al., 1999). In analogy with observations in yeast it has also been proposed that by binding either PI, PC or SPM, PI-TPs act as regulators of phospholipid metabolism at distinct sites in the cell thereby fulfilling the roles of biosensors (McGee