Membrane contact site

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Membrane contact sites (MCS) are close appositions between two organelles. Ultrastructural studies typically reveal an intermembrane distance in the order of the size of a single protein, as small as 10 nm or wider, with no clear upper limit. These zones of apposition are highly conserved in evolution.[1] These sites are thought to be important to facilitate signalling, and they promote the passage of small molecules, including ions, lipids[2] and (discovered later) reactive oxygen species.[3][4] MCS are important in the function of the endoplasmic reticulum (ER),[5] since this is the major site of lipid synthesis within cells.[6] The ER makes close contact with many organelles, including mitochondria, Golgi, endosomes, lysosomes, peroxisomes, chloroplasts and the plasma membrane.[7] Both mitochondria and sorting endosomes undergo major rearrangements leading to fission where they contact the ER.[5] Sites of close apposition can also form between most of these organelles most pairwise combinations.[8] First mentions of these contact sites can be found in papers published in the late 1950s mainly visualized using electron microscopy (EM) techniques. Copeland and Dalton described them as “highly specialized tubular form of endoplasmic reticulum in association with the mitochondria and apparently in turn, with the vascular border of the cell”.[9]

Plasma membrane - endoplasmic reticulum contact sites[edit]

MCSs between ER and PM exist in different cell types from neurons to muscle cells, from Homo sapiens to Saccharomyces cerevisiae. Some studies showed that more than 1000 contact sites are present in every yeast cell and the distance between the lipid bilayer ranges from 10 to 25 nm (the order of the size of a single protein). PM-ER contact sites have been linked to the main functions of MCS: lipid synthesis, lipid trafficking, and calcium homeostasis.[3] A set of molecular tools (e.g., LiMETER and MAPPER) have been developed to label and manipulate the formation of ER-PM junctions in living cells.[10][11]

Lipid biosynthesis[edit]

The uneven distribution of sterols among the membranes of the cell organelles, depends largely on non-vesicular route of transfer. For instance, in the ER, where they are synthetised, they account for about the 5%, but they are far more concentrated in the PM, where they account for more than 30% of lipid content.[12]

Because lipids are insoluble in water (for example sterols <100 nM), and the spontaneous interbilayer and transbilayer lipid movement has halftime ranging from 1-2 h up to 103 h, it is generally accepted that the lipid trafficking must be mediated by lipid transfer proteins (LTPs) alongside the vesicular trafficking, which is not a major route for sterols. Several families of LTPs have been identified: they can carry the lipid molecule shielding its lipophilic chains from the aqueous ambient of the cytosol.[7]

OSBP is the most extensively studied member of the oxysterol-binding protein (OSBP) related proteins family (ORP). It was first described as the cytoplasmic receptor for 25-hydroxycholesterol,[13] and after more than 20 years it was shown that it's a cholesterol regulated protein in complex with ERK.[14] Now, after the description of the structural basis for sterol sensing and transport,[15] ORP protein family members are known to be essential for sterol signalling and sterol transport functions. Their peculiar structure is characterized by a conserved β-barrel sterol-binding fold with additional domains that can target multiple organelle membranes.

In yeast, Osh4 is an OSBP homologue the crystal structure of which, obtained in both the sterol-bound and unbound states, showed a soluble β-barrel protein with a hydrophilic external surface and a hydrophobic pocket that can carry a single sterol molecule. Seven OSBP homologues (OSH proteins) have been identified in Saccharomyces cerevisiae, in which their role has been suggested to be more relevant to sterol organization in the PM, rather than sterol trafficking from ER.[3] Furthermore, Stefan et al. showed that OSH proteins control PI4P metabolism via the Sac1 Phosphatidylinositol (PI) 4-phosphatase. They also proposed a mechanism for Sac1 regulation: high Phosphatidylinositol 4-phosphate (PI4P) levels on the plasma membrane recruit Osh3 at PM-ER contact sites through its pleckstrin homology (PH) domain; Osh3 is now active and can interact with the ER-resident VAP proteins Scs2/Scs22 through its FFAT motif (two phenylalanines on an acidic tract), ultimately activating ER-localized Sac1 to reduce PI levels.[16]

The VAMP-associated proteins (VAPs) are highly conserved integral ER membrane proteins involved in different cellular functions. They localize to the ER, and their ability to interact with multiple lipid-transfer, lipid-binding or lipid-sensing proteins containing the FFAT motif, suggests that VAPs have a role in lipid transport at the MCSs. Scs2 interacts with Osh1, Osh2 and Osh3. Different VAPs may be the partners at contact sites between different organelles.[17][18]

Calcium homeostasis[edit]

PM-ER contact sites have a well known role in the control of calcium dynamics. The major intracellular pool of calcium is the ER and its release may be triggered by different stimuli. In excitable cells the coupling between PM depolarization and the release from the intracellular pools is essential to generate the Ca2+ signalling. In muscle cells, at the triad, junctophilin, an integral ER membrane protein, is involved in ER-PM contact stabilization by interacting with PIPs in the PM. In these contact sites, voltage-gated Ca2+ channels (VGCCs) activate closely apposed ryanodine receptors expressed on the ER to trigger calcium release during excitation-contraction coupling. However, calcium levels need to be tightly controlled in all cell types. Non-excitable cells regulate calcium influx through PM calcium channels by sensing luminal ER calcium levels (the Calcium Release Activated Channels). ORAI1 is a molecular component of the CRAC, and it interacts with STIM1 an ER protein. STIM1 can rapidly translocate to a PM-ER contact site after depletion of the ER stores.[3]

Mitochondria - endoplasmic reticulum contact sites[edit]

Contact sites between the outer mitochondrial membrane and the ER is present in many organisms.[2] About 100 of these contact sites exist between the ER and mitochondria per yeast cell.[3] The fraction of ER that co-purifies with mitochondria, the so-called Mitochondria-associated endoplasmic reticulum membrane (MAM) has been extensively studied during the last decade. In the "MAM hypothesis" it has been proposed that at the centre of the pathogenesis of Alzheimer's disease resides the disorder of ER-mitochondrial contact sites rather than Amyloid plaques or Neurofibrillary tangles.[19]

Lipid biosynthesis[edit]

The presence of enzymes involved in phospholipid biosynthesis in MAM fraction is known since the 1970s, and the synthesis of some phospholipid is completed in both organelles. For instance, the biosynthetic pathway of phosphatidylcholine involves different steps some on the ER and some on the inner mitochondrial membrane. Connerth et al. identified Ups1 as a yeast LTP that can shuttle phosphatidic acid (PA) between mitochondrial membranes: they showed that effective lipid transfer required the interaction of Ups1 with Mdm35 to convert phosphatidic acid into cardiolipin in the inner membrane. Furthermore, they suggested the existence of a regulatory feedback mechanism that limits the accumulation of cardiolipin in mitochondria: high cardiolipin concentrations have the final results to inhibit its synthesis and the mitochondrial import of PA.[20] Another study by Lahiri et al. has demonstrated that loss of contacts between the ER and mitochondria results in severe reduction in mitochondrial biosynthesis of phosphatidylethanolamine (PE) due to reduction in transport of phosphatidylserine (PS), which is the precursor for PE synthesis.[21]

See also[edit]

References[edit]

  1. ^ Levine T (September 2004). "Short-range intracellular trafficking of small molecules across endoplasmic reticulum junctions". Trends in Cell Biology. 14 (9): 483–90. doi:10.1016/j.tcb.2004.07.017. PMID 15350976.
  2. ^ a b Prinz, William A.; Choudhary, Vineet; Liu, Li-Ka; Lahiri, Sujoy; Kannan, Muthukumar (2017-03-01). "Phosphatidylserine synthesis at membrane contact sites promotes its transport out of the ER". Journal of Lipid Research. 58 (3): 553–562. doi:10.1194/jlr.M072959. ISSN 0022-2275. PMC 5335585. PMID 28119445.
  3. ^ a b c d e Elbaz Y, Schuldiner M (November 2011). "Staying in touch: the molecular era of organelle contact sites". Trends in Biochemical Sciences. 36 (11): 616–23. doi:10.1016/j.tibs.2011.08.004. PMID 21958688.
  4. ^ Csordás G, Weaver D, Hajnóczky G (July 2018). "Endoplasmic Reticulum-Mitochondrial Contactology: Structure and Signaling Functions". Trends in Cell Biology. 28 (7): 523–540. doi:10.1016/j.tcb.2018.02.009. PMC 6005738. PMID 29588129.
  5. ^ a b Phillips MJ, Voeltz GK (February 2016). "Structure and function of ER membrane contact sites with other organelles". Nature Reviews. Molecular Cell Biology. 17 (2): 69–82. doi:10.1038/nrm.2015.8. PMC 5117888. PMID 26627931.
  6. ^ Voeltz GK, Rolls MM, Rapoport TA (October 2002). "Structural organization of the endoplasmic reticulum". EMBO Reports. 3 (10): 944–50. doi:10.1093/embo-reports/kvf202. PMC 1307613. PMID 12370207.
  7. ^ a b Helle SC, Kanfer G, Kolar K, Lang A, Michel AH, Kornmann B (November 2013). "Organization and function of membrane contact sites". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1833 (11): 2526–41. doi:10.1016/j.bbamcr.2013.01.028. PMID 23380708.
  8. ^ Bohnert M, Schuldiner M (May 2018). "Stepping outside the comfort zone of membrane contact site research". Nature Reviews. Molecular Cell Biology. 19 (8): 483–484. doi:10.1038/s41580-018-0022-1. PMC 6287737. PMID 29765158.
  9. ^ Copeland DE, Dalton AJ (May 1959). "An association between mitochondria and the endoplasmic reticulum in cells of the pseudobranch gland of a teleost". The Journal of Biophysical and Biochemical Cytology. 5 (3): 393–6. doi:10.1083/jcb.5.3.393. PMC 2224680. PMID 13664679.
  10. ^ Jing J, He L, Sun A, Quintana A, Ding Y, Ma G, Tan P, Liang X, Zheng X, Chen L, Shi X, Zhang SL, Zhong L, Huang Y, Dong MQ, Walker CL, Hogan PG, Wang Y, Zhou Y (October 2015). "Proteomic mapping of ER-PM junctions identifies STIMATE as a regulator of Ca²⁺ influx". Nature Cell Biology. 17 (10): 1339–47. doi:10.1038/ncb3234. PMC 4589512. PMID 26322679.
  11. ^ Chang CL, Hsieh TS, Yang TT, Rothberg KG, Azizoglu DB, Volk E, Liao JC, Liou J (November 2013). "Feedback regulation of receptor-induced Ca2+ signaling mediated by E-Syt1 and Nir2 at endoplasmic reticulum-plasma membrane junctions". Cell Reports. 5 (3): 813–25. doi:10.1016/j.celrep.2013.09.038. PMID 24183667.
  12. ^ Mesmin B, Antonny B, Drin G (September 2013). "Insights into the mechanisms of sterol transport between organelles". Cellular and Molecular Life Sciences. 70 (18): 3405–21. doi:10.1007/s00018-012-1247-3. PMID 23283302. S2CID 18302513.
  13. ^ Kandutsch AA, Thompson EB (November 1980). "Cytosolic proteins that bind oxygenated sterols. Cellular distribution, specificity, and some properties". The Journal of Biological Chemistry. 255 (22): 10813–21. doi:10.1016/S0021-9258(19)70380-9. PMID 7430156.
  14. ^ Wang PY, Weng J, Anderson RG (March 2005). "OSBP is a cholesterol-regulated scaffolding protein in control of ERK 1/2 activation". Science. 307 (5714): 1472–6. Bibcode:2005Sci...307.1472W. doi:10.1126/science.1107710. PMID 15746430. S2CID 24956100.
  15. ^ Im YJ, Raychaudhuri S, Prinz WA, Hurley JH (September 2005). "Structural mechanism for sterol sensing and transport by OSBP-related proteins". Nature. 437 (7055): 154–8. Bibcode:2005Natur.437..154I. doi:10.1038/nature03923. PMC 1431608. PMID 16136145.
  16. ^ Stefan CJ, Manford AG, Baird D, Yamada-Hanff J, Mao Y, Emr SD (February 2011). "Osh proteins regulate phosphoinositide metabolism at ER-plasma membrane contact sites". Cell. 144 (3): 389–401. doi:10.1016/j.cell.2010.12.034. PMID 21295699.
  17. ^ Lev S, Ben Halevy D, Peretti D, Dahan N (June 2008). "The VAP protein family: from cellular functions to motor neuron disease". Trends in Cell Biology. 18 (6): 282–90. doi:10.1016/j.tcb.2008.03.006. PMID 18468439.
  18. ^ Lahiri S, Toulmay A, Prinz WA (April 2015). "Membrane contact sites, gateways for lipid homeostasis". Current Opinion in Cell Biology. 33: 82–87. doi:10.1016/j.ceb.2014.12.004. PMC 4380522. PMID 25569848.
  19. ^ Schon EA, Area-Gomez E (July 2013). "Mitochondria-associated ER membranes in Alzheimer disease". Molecular and Cellular Neurosciences. 55: 26–36. doi:10.1016/j.mcn.2012.07.011. PMID 22922446.
  20. ^ Connerth M, Tatsuta T, Haag M, Klecker T, Westermann B, Langer T (November 2012). "Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein". Science. 338 (6108): 815–8. Bibcode:2012Sci...338..815C. doi:10.1126/science.1225625. PMID 23042293. S2CID 206542939.
  21. ^ Lahiri S, Chao JT, Tavassoli S, Wong AK, Choudhary V, Young BP, Loewen CJ, Prinz WA (October 2014). "A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria". PLOS Biology. 12 (10): e1001969. doi:10.1371/journal.pbio.1001969. PMC 4196738. PMID 25313861.
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