Biology:PITPNM3

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Short description: A mammalian lipid transfer protein

Nir1 or membrane-associated phosphatidylinositol transfer protein 3 (PITPNM3) is a mammalian protein that localizes to endoplasmic reticulum (ER) and plasma membrane (PM) membrane contact sites (MCS) and aids the transfer of phosphatidylinositol between these two membranes, potentially by recruiting additional proteins to the ER-PM MCS. It is encoded by the gene PITPNM3.[1]

Classification

Nir1 has been classically categorized as a class IIA phosphatidylinositol transfer protein (PITP) that transfers phosphatidylinositol (PI) and phosphatidic acid (PA) between membranes. Class IIA PITPs are the multi-domain proteins PITPNM1/Nir2 (Drosophila homolog RdgBaI), PITPNM2/Nir3 (Drosophila homolog RdgBaII)..[2][3] Nir1 shares high sequence similarity with Nir2 and Nir3, which led to its original categorization as a PITP. However, it was determined that Nir1 is not directly responsible for PI transfer, as it lacks the functional PITP domain seen within Nir2 and Nir3[3]

The names, Drosophila homologs, and domain architecture of the PITPNM family proteins.

Localization

Recently, Nir1 has been shown to localize to ER-PM MCS, both under basal conditions and upon phospholipase C (PLC) activation. Notably, PLC activation has previously been shown to regulate the localization of Nir2 and Nir3 at ER-PM MCS well..[4][5] The MCS-targeting by Nir1 is achieved by the N-terminus of Nir1 localizing to the ER and the C-terminus of Nir1 localizing to the PM. The domains responsible for binding these membranes are discussed below.

Structure

Nir1 contains three main structural elements that are shared with Nir2 and Nir3: an N-terminal FFAT motif, a DDHD domain, and a C-terminal Lipin/Ndel/Smp2 (LNS2) domain.[6]

FFAT motif

The FFAT motif is made up of double phenylalanines (FF) in an Acidic Tract. This motif, made of residues EFFDA in Nir1, has been shown to be necessary for the Nir proteins to associate with the ER proteins VAPA and VAPB. Mutation of the phenylalanine residues in this motif or knockout of the VAPA and VAPB proteins results in a loss of ER-PM MCS localization and causes Nir1 to become fully localized to the PM.[4][5]

DDHD domain

The DDHD domain, made up of 3 Asp and 1 His residues, bears some similarities to that seen in PLA1 enzymes, which hydrolyze fatty acids of glycerolphospholipids, including phosphatidic acid (PA). However, this domain is still largely uncharacterized. It is a putative metal binding domain, but a role for metal binding in PITPNM function has not been established[3][7][8]

LNS2 domain

The LNS2 domain is the Lipin/Nde1/Smp2 domain. This domain was discovered as having sequence similarities to the phosphatidic acid (PA) binding region found within the Lipin family of proteins.[9] It is also responsible for PA-binding within Nir1, as it has been shown to co-localize with PA biosensors. The LNS2 domain targets the C-terminus of Nir1 to the plasma membrane in order to allow the protein to bridge the ER-PM MCS. Deletion of this domain results in Nir1 localization to the ER.[4][5] It should be noted however, that the exact domain boundaries of the LNS2 domain are still being debated, especially given the boundaries of the folded domains predicted by the AlphaFold Protein Structure Database.[10][11] (Alphafold structure of Nir1)

Function

The PITPNM family of proteins has been shown to participate in the phosphoinositide cycle. Lipids cycle between the PM and the ER in order to replenish levels after signaling events deplete lipid species such as PI..[2] When a stimulus results in the production of PA at the PM, Nir2 and Nir3 move to the ER-PM MCS, where they exchange the PA at the PM for PI that has been produced in the ER. As Nir1 is localized to the ER-PM MCS even without a stimulus, it is thought that Nir1 helps to recruit Nir2 to the MCS. There is evidence that Nir1 recruits Nir2 directly via binding to the uncharacterized domain between the FFAT and DDHD of Nir1[4][5]

Nir1 localizes to ER-PM MCS using its FFAT and LNS2 domains. It is thought to directly interact with Nir2 in order to recruit Nir2 to the ER-PM MCS, so that Nir2 can transfer lipids with its PITP domain.

References

  1. ↑ "PITPNM3 Gene - PITPNM Family Member 3". 4 October 2023. https://www.genecards.org/cgi-bin/carddisp.pl?gene=PITPNM3&keywords=PITPNM3. 
  2. ↑ 2.0 2.1 Cockcroft, Shamshad; Raghu, Padinjat (2016-11-25). "Topological organisation of the phosphatidylinositol 4,5-bisphosphate–phospholipase C resynthesis cycle: PITPs bridge the ER–PM gap". Biochemical Journal 473 (23): 4289–4310. doi:10.1042/bcj20160514c. ISSN 0264-6021. PMID 27888240. http://dx.doi.org/10.1042/bcj20160514c. 
  3. ↑ 3.0 3.1 3.2 Balla, Tamas (July 2013). "Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation". Physiological Reviews 93 (3): 1019–1137. doi:10.1152/physrev.00028.2012. ISSN 0031-9333. PMID 23899561. PMC 3962547. http://dx.doi.org/10.1152/physrev.00028.2012. 
  4. ↑ 4.0 4.1 4.2 4.3 Quintanilla, Carlo Giovanni; Lee, Wan-Ru; Liou, Jen (2022-03-01). Olzmann, James. ed. "Nir1 constitutively localizes at ER–PM junctions and promotes Nir2 recruitment for PIP 2 homeostasis" (in en). Molecular Biology of the Cell 33 (3): br2. doi:10.1091/mbc.E21-07-0356. ISSN 1059-1524. PMID 35020418. 
  5. ↑ 5.0 5.1 5.2 5.3 Chang, Chi-Lun; Liou, Jen (June 2015). "Phosphatidylinositol 4,5-Bisphosphate Homeostasis Regulated by Nir2 and Nir3 Proteins at Endoplasmic Reticulum-Plasma Membrane Junctions". Journal of Biological Chemistry 290 (23): 14289–14301. doi:10.1074/jbc.m114.621375. ISSN 0021-9258. PMID 25887399. 
  6. ↑ Cockcroft, Shamshad; Lev, Sima (January 2020). "Mammalian PITPs at the Golgi and ER-Golgi Membrane Contact Sites". Contact 3: 251525642096417. doi:10.1177/2515256420964170. ISSN 2515-2564. 
  7. ↑ Ile, Kristina E; Schaaf, Gabriel; Bankaitis, Vytas A (2006-10-18). "Phosphatidylinositol transfer proteins and cellular nanoreactors for lipid signaling". Nature Chemical Biology 2 (11): 576–583. doi:10.1038/nchembio835. ISSN 1552-4450. PMID 17051233. http://dx.doi.org/10.1038/nchembio835. 
  8. ↑ Matsumoto, Naoki; Nemoto-Sasaki, Yoko; Oka, Saori; Arai, Seisuke; Wada, Ikuo; Yamashita, Atsushi (July 2021). "Phosphorylation of human phospholipase A1 DDHD1 at newly identified phosphosites affects its subcellular localization". Journal of Biological Chemistry 297 (1): 100851. doi:10.1016/j.jbc.2021.100851. ISSN 0021-9258. PMID 34089703. 
  9. ↑ Kim, SoHui; Kedan, Amir; Marom, Merav; Gavert, Nancy; Keinan, Omer; Selitrennik, Michael; Laufman, Orly; Lev, Sima (2013-07-30). "The phosphatidylinositol‐transfer protein Nir2 binds phosphatidic acid and positively regulates phosphoinositide signalling". EMBO Reports 14 (10): 891–899. doi:10.1038/embor.2013.113. ISSN 1469-221X. PMID 23897088. PMC 3807235. http://dx.doi.org/10.1038/embor.2013.113. 
  10. ↑ Varadi, Mihaly; Anyango, Stephen; Deshpande, Mandar; Nair, Sreenath; Natassia, Cindy; Yordanova, Galabina; Yuan, David; Stroe, Oana et al. (2021-11-17). "AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models". Nucleic Acids Research 50 (D1): D439–D444. doi:10.1093/nar/gkab1061. ISSN 0305-1048. PMID 34791371. PMC 8728224. http://dx.doi.org/10.1093/nar/gkab1061. 
  11. ↑ Jumper, John; Evans, Richard; Pritzel, Alexander; Green, Tim; Figurnov, Michael; Ronneberger, Olaf; Tunyasuvunakool, Kathryn; Bates, Russ et al. (2021-07-15). "Highly accurate protein structure prediction with AlphaFold". Nature 596 (7873): 583–589. doi:10.1038/s41586-021-03819-2. ISSN 0028-0836. PMID 34265844. PMC 8371605. Bibcode: 2021Natur.596..583J. http://dx.doi.org/10.1038/s41586-021-03819-2. 



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