PROSITE documentation PDOC52086

PITP-like domain profile

Phosphatidylinositol transfer proteins (PITPs) constitute a highly conserved family of proteins found in many organisms, including mammals, Caenorhabditis elegans (worms), Drosophila melanogaster (flies), and Dictyostelium discoideum (slime molds), but not in yeasts or plants. The PITP family is one of the two families of phosphoinositide transfer proteins that can bind and exchange one molecule of either phosphatidylinositol or phosphatidylcholine and facilitate the transfer of these lipids between different membrane compartments; the other is the structurally unrelated Sec14p family. PITPs are critical regulators of phosphoinositides in several cellular compartments, where they participate in signal transduction and in membrane traffic. To transfer a phospholipid, PITP must first bind to the membrane, exchange its bound lipid for a membrane lipid, and then dissociate from the membrane. The PITP-like domain is required to facilitate the exchange of phosphatidylinositol and phosphatidic acid at their associated membranes [1,2,3].

Three subfamilies can be defined and all isoforms have an amino-terminal PITP-like domain comprising ~260 amino acids. All three types occur in humans: the first comprises the small PITPα and PITPβ proteins; the second comprises the large rdgBα (also called M-RdgB1, Nir2 and PITPnm) and Nir3 (also called M-RdgB2) proteins; and the third type comprises the rdgBβ protein, which is intermediate in size and was identified by homology to rdgBα. The rdgB acronym is derived from a retinal degeneration mutant phenotype (type B) in Drosophila, and the Nir acronym is derived from a reported interaction with the amino-terminal domain of the Pyk2 tyrosine kinase (Pyk2 N-terminal domain-interacting receptor). A third protein, termed Nir1, was also identified, but this lacks a PITP domain [1,2].

The amino acid sequence of the PITP-like domain is highly conserved in all isoforms and no characteristic short sequence motifs have been identified. The prominent structural features of PITP-like domains include a large concave β-sheet and several long helices (see <PDB:1T27>). The amino-terminal lipid-binding region contains the most highly conserved residues. It contains an eight-stranded, concave, mostly antiparallel β-sheet and two helices, which encircle the bound lipid and are structurally homologous to the START family of lipid-binding proteins (see <PDOC50848>). A lipid exchange loop which contains a small helix acts as a lid to the lipid-binding cavity. A regulatory loop is likely required for the association of PITP-like domains with a wide variety of lipid- and protein-modifying enzymes. The carboxy-terminal helical region of the PITP-like domain shows greatest sequence variation and may play an important role in membrane binding [2,3,4,5].

The profile we developed covers the entire PITP-like domain.