PROSITE documentation PDOC52092

Lipin/Ned1/Smp2 (LNS2)-associated immunoglobulin (Ig)-like domain profiles

Phosphatidic acid (PA) is a truly versatile lipid, with parallel activities as a vital metabolic intermediate, a second messenger, and a determinant of unique membrane properties. PA serves as a precursor for lipid species such as diacylglycerol (DAG), lysophosphatidic acid, and CDP-DAG, each of which is used in its own signaling and metabolic pathways. The lipin/Ned1/Smp2 (LNS2) domain of 180 amino acids, originally characterized as the Mg(2+)-dependent catalytic domain of PA phosphatases (lipins), is catalytically inactive in Nir proteins and RdgBα that exhibit substitutions for a critical catalytic aspartate residue and another Mg(2+)-coordinating residue (see <PDOC52087>). Both protein families also contain an immunoglobulin (Ig)-like domain which is generally split in the lipin family. It has been suggested that the LNS2-associated Ig-like domain contributes at least partially to membrane binding [1,2,3,4,5,6].

The LNS2-associated Ig-like domain differs significantly from canonical Ig domains which form a two-layered β-sandwich (see <PDB:9JZP>) made of seven β-strands, labeled A-G. The most prominent difference occurs at the βE strand, which splays outward away from the β-sandwich core and forms a β-hairpin with a βE' strand. A small helical insert immediately following the βE' strand connects back to the canonical βF and βG strands to complete the β-sandwich. Notably, the transition between the N- and C-terminal parts of the split Ig-like domains found in the lipin family occurs directly at the turn in the β-hairpin formed by the βE and βE' strands, which can be separated by an extended 250-500 residue linker [4,5,6].

Protein families known to contain a LNS2-associated Ig-like domain are listed below:

• Lipin/Pah phosphatidic acid phosphatases (PAPs) are Mg(2+)-dependent enzymes that catalyze the dephosphorylation of PA to produce diacylglycerol. Lipin/Pah PAPs regulate energy storage, energy mobilization, adipogenesis, phospholipid synthesis, autophagy, chylomicron secretion, and fatty acid synthesis. The architecture of lipin/Pah PAPs varies, but all PAPs contain two highly conserved N-Lip and C-Lip regions that combine to form two domains: the split Ig-like domain and the catalytic LNS2 domain. Lipin/Pah are evolutionarily conserved from yeast to humans. There are three lipin paralogs with multiple splicing variants in humans and mice, one PA phosphohydrolase (Pah, previously known as Smp2) in Saccharomyces cerevisiae, and two Pah enzymes (Pah1 and Pah2) in the ciliate Tetrahymena thermophila [5,6].
• Class IIA phosphatidylinositol transfer proteins (PITPs), the PITPNM/Nir/ RdgB subfamily, regulate basal levels of phosphatidylinositol (4,5)- bisphosphate (PI(4,5)P(2)) at the plasma membrane. The official name is PITPNM; the nomenclature "RdgB" originates from the prototypical Drosophila PITP associated with retinal degeneration, whereas "Nir" nomenclature refers to their initial identification as PYK2 N-terminal domain- interacting receptors. In mammals, there are two Nir proteins (Nir2 and Nir3), whilst Drosophila expresses a single protein. Class IIA proteins (e.g. Nir2, Nir3 and RdgBα) are multidomain proteins which share a common domain architecture comprising an N-terminal PITP domain (see <PDOC52086>), a FFAT motif, a DDHD (see <PDOC51043>) and a C-terminal LNS2 domain. The PITPNM LNS2 domains exhibit substitutions for a critical catalytic aspartate residue and therefore lack PAP-activity [2,3,4].
• Nir1 (encoded by Pitpnm3) is structurally related to Class IIA proteins but lacks the PITP domain. It acts as a scaffold that facilitates Nir2 recruitment to endoplasmic reticulum (ER)-PM contact sites [1].

We developed three profiles for the LNS2-associated Ig-like domain. The first one covers the entire PITPNM/Nir/RdgB LNS2-associated Ig-like domain. The second and third cover respectively the N- and C-terminal parts of the generally split lipin LNS2-associated Ig-like domain.