Endoplasmic reticulum membrane protein complex

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Endoplasmic reticulum membrane protein complex
Identifiers
SymbolEMC
Membranome637

The endoplasmic reticulum membrane protein complex (EMC) is a putative endoplasmic reticulum-resident membrane protein (co-)chaperone.[1] The EMC is evolutionarily conserved in eukaryotes (animals, plants, and fungi), and its initial appearance might reach back to the last eukaryotic common ancestor (LECA).[2] Many aspects of mEMC biology and molecular function remain to be studied.

Composition and structure[edit]

The EMC consists of up to 10 subunits (EMC1 - EMC4, MMGT1, EMC6 - EMC10), of which only two (EMC8/9) are homologous proteins.[3][2] Seven out of ten (EMC1, EMC3, EMC4, MMMGT1, EMC6, EMC7, EMC10) subunts are predicted to contain at least one transmembrane domain (TMD), whereas EMC2, EMC8 and EMC9 do not contain any predicted transmembrane domains are herefore likely to interact with the rest of the EMC on the cytosolic face of the endoplasmic reticulum (ER). EMC proteins are thought to be present in the mature complex in a 1:1 stoichiometry.[4][5]

Subunit primary structure[edit]

The majority of EMC proteins (EMC1/3/4/MMGT1/6/7/10) contain at least one predicted TMD. EMC1, EMC7 and EMC10 contain an N-terminal signal sequence.

EMC1[edit]

EMC1, also known as KIAA0090, contains a single TMD (aa 959-979) and Pyrroloquinoline quinone (PQQ)-like repeats (aa 21-252), which could form a β-propeller domain.[6][7] The TMD is part of a domain a larger domain (DUF1620).[8][7] The functions of the PQQ and DUF1620 domains in EMC1 remain to be determined.

EMC2[edit]

EMC2 (TTC35) harbours three tetratricopeptide repeats (TPR1/2/3). TPRs have been shown to mediate protein-protein interactions and can be found in a large variety of proteins of diverse function.[9][10][11] The function of TPRs in EMC2 is unknown.

EMC8 and EMC9[edit]

EMC8 and EMC9 show marked sequence identity (44.72%) on the amino acid level. Both proteins are members of the UPF0172 family, a member of which (e.g. TLA1) are involved in regulating the antenna size of chlorophyll-a.[12][13][14]

Posttranslational modifications[edit]

Several subunits of the mammalian EMC (mEMC) are posttranslationally modified. EMC1 contains three predicted N-glycosylation sites at positions 370, 818, and 913.[6] EMC10 features a predicted N-glycosylation consensus motif at position 182.

Evolutionary conservation[edit]

EMC proteins are evolutionarily conserved in eukaryotes.[2] No homologues are reported in prokaryotes. Therefore, the EMC has been suggested to have its evolutionary roots in the last eukaryote common ancestor (LECA).[2]

Function[edit]

Protein folding and degradation at the ER[edit]

The EMC was first identified in a genetic screen in yeast for factors involved in protein folding in the ER.[1] Accordingly, deletion of individual EMC subunits correlates with the induction of an ER stress response in various model organisms.[1][15][16] However, it is worth noting that in human osteosarcoma cells (U2OS cells), deletion of EMC6 does not appear to cause ER stress.[17][18] When overexpressed, several subunits of the mammalian EMC orthologue (mEMC) have been found to physically interact with ERAD components (UBAC2, DER1, DER2)[3] Genetic screens in yeast have shown EMC subunits to be enriched in alongside ERAD genes.[19][20] Taken together, these findings imply a role of the mEMC in protein homeostasis.

Chaperone[edit]

Maturation of polytopic membrane proteins[edit]

Several lines of evidence implicate the EMC in promoting the maturation of polytopic membrane proteins. The EMC is necessary to correctly and efficiently insert the first transmembrane domain (also called the signal anchor) of G-protein coupled receptors (GPCRs) such as the beta-adrenergic receptor.[21] Determining features of transmembrane domains that favour EMC involvement seem to be moderate hydrophobicity and ambiguous distribution of TMD flanking charges.

The substrate spectrum of the EMC appears to extend beyond GPCRs. Unifying properties of putative EMC clients are the presence of unusually hydrophilic transmembrane domains containing charged residues.[22] However, mechanistic detail of how the EMC assists in orienting and inserting such problematic transmembrane domains is lacking. In many cases, evidence implicating the EMC in the biogenesis of a certain protein consists of co-depletion when individual subunts of the EMC are disrupted.

A number of putative EMC clients are listed below, but the manner in which the EMC engages them and whether they directly or indirectly depend on the EMC merits further investigation:

Loss of EMC function destabilises the enzyme sterol-O-acyltransferase 1 (SOAT1) and, in conjunction with overlooking the biogenesis of squalene synthase (SQS), helps to maintain cellular cholesterol homeostasis.[23] SOAT1 is an obligatory enzyme for cellular cholesterol storage and detoxification. For SQS, an enzyme controlling the committing step in cholesterol biosynthesis, the EMC has been shown to be sufficient for its integration into liposomes in vitro.[24]

Depletion of EMC6 and additional EMC proteins reduces the cell surface expression of the nicotinic Acetylcholine receptors in C. elegans.[15]

Knockdown of EMC2 has been observed to correlate with decreased CFTRΔF508 levels.[25] EMC2 contains three tetratricopeptide repeat domains (TRPs). TRPs have been shown to mediate protein-protein interaction and can be found in co-chaperones of Hsp90. Therefore, a role of EMC2 in mediating interactions with cytosolic chaperones is conceivable, but remains to be demonstrated.

Loss of EMC subunits in D. melanogaster correlates with strongly reduced cell surface expression of rhodopsin-1 (Rh1), an important polytopic light receptor in the plasma membrane.[16]

In yeast, the EMC has been implicated in maturation or trafficking defects of the polytopic model substrate Mrh1p-GFP.[26]

Recently, structural and functional studies have identified a holdase function for the EMC in the assembly and maturation of the voltage gated calcium channel CaV1.2.[27]

Insertion proteins into the ER[edit]

The EMC was shown to be involved in a pathway mediating the membrane integration of tail-anchored proteins containing an unusually hydrophilic or amphiphatic transmembrane domains.[24] This pathway appears to operate in parallel to the conventional Get/Trc40 targeting pathway.

Other suggested functions[edit]

Mitochondrial tethering[edit]

In S. cerevisiae, the EMC has been reported by Lahiri and colleagues to constitute a tethering complex between the ER and mitochondria.[28] Close apposition of both organelles is a prerequisite for phosphatidylcholine (PS) biosynthesis in which phosphatidylserine (PS) is imported from the ER into mitochondria, and this was previously proposed as evidence for a membrane tether between these two organelles by Jean Vance.[29][30] Disruption of the EMC by genetic deletion of multiple of its subunits was shown to reduce ER-mitochondrial tethering and to impair transfer of phosphatidylserine (PS) from the ER.[28]

Autophagosome formation[edit]

EMC6 interacts with the small GTPase RAB5A and Beclin-1, regulators of autophagosome formation.[17][18] This observation suggests that the mEMC, and not just EMC6, might be involved in regulating Rab5A and BECLIN-1. However, the molecular mechanism underlying the proposed modulation of autophagosome formation remains to be established.

Involvement in disease[edit]

The mEMC has repeatedly been implicated in a range of pathologies including susceptibility of cells to viral infection, cancer, and a congenital syndrome of severe physical and mental disability. None of these pathologies seem to be related by disruption of a single molecular pathway that might be regulated by the mEMC. Consequently, the involvement of the mEMC in these pathologies has only limited use for defining the primary function of this complex.

As a host factor in viral infections[edit]

Large-scale genetic screens imply several mEMC subunits in modulating the pathogenicity of flaviviruses such as West Nile virus (WNV), Zika virus (ZV), Dengue fever virus (DFV), and yellow fever virus (YFV).[20][31] In particular, loss of several mEMC subunits (e.g. EMC2, EMC3) lead to inhibition of WNV-induced cell death. however, WNV was still able to infect and proliferate in cells lacking EMC subunits.[20] The authors made a similar observation of the role of the mEMC in the cell-killing capacity of Saint Louis Encephalitis Virus. The underlying cause for the resistance of EMC2/3-deficient cells to WNV-induced cytotoxicity remains elusive.

Cancer[edit]

Dysregulation of individual mEMC subunits correlates with the severity of certain types of cancer. Expression of hHSS1, a secreted splice variant of EMC10 (HSM1), reduces the proliferation and migration of glioma cell lines.[32]

Overexpression of EMC6 has been found to reduce cell proliferation of glioblastoma cells in vitro and in vivo, whereas its RNAi-mediated depletion has the opposite effect.[18] This indicates that the mEMC assumes (an) important function(s) in cancerous cells to establish a malignant tumour.

Pathologies[edit]

Mutations in the EMC1 gene have been associated with retinal dystrophy and a severe systemic disease phenotype involving developmental delay, cerebellar atrophy, scoliosis and hypotonia.[33]

Similarly, a homozygous missense mutation (c.430G>A, p.Ala144Thr) within the EMC1 gene has been correlated with the development of retinal dystrophy.[34]

Even though a set of disease-causing mutations in EMC1 has been mapped, their effect on EMC1 function and structure remain to be studied.

References[edit]

  1. ^ a b c Jonikas MC, Collins SR, Denic V, Oh E, Quan EM, Schmid V, Weibezahn J, Schwappach B, Walter P, Weissman JS, Schuldiner M (March 2009). "Comprehensive characterization of genes required for protein folding in the endoplasmic reticulum". Science. 323 (5922): 1693–7. Bibcode:2009Sci...323.1693J. doi:10.1126/science.1167983. PMC 2877488. PMID 19325107.
  2. ^ a b c d Wideman JG (25 August 2015). "The ubiquitous and ancient ER membrane protein complex (EMC): tether or not?". F1000Research. 4: 624. doi:10.12688/f1000research.6944.2. PMC 4602282. PMID 26512320.
  3. ^ a b Christianson JC, Olzmann JA, Shaler TA, Sowa ME, Bennett EJ, Richter CM, Tyler RE, Greenblatt EJ, Harper JW, Kopito RR (November 2011). "Defining human ERAD networks through an integrative mapping strategy". Nature Cell Biology. 14 (1): 93–105. doi:10.1038/ncb2383. PMC 3250479. PMID 22119785.
  4. ^ Li GW, Burkhardt D, Gross C, Weissman JS (April 2014). "Quantifying absolute protein synthesis rates reveals principles underlying allocation of cellular resources". Cell. 157 (3): 624–35. doi:10.1016/j.cell.2014.02.033. PMC 4006352. PMID 24766808.
  5. ^ Hein MY, Hubner NC, Poser I, Cox J, Nagaraj N, Toyoda Y, Gak IA, Weisswange I, Mansfeld J, Buchholz F, Hyman AA, Mann M (October 2015). "A human interactome in three quantitative dimensions organized by stoichiometries and abundances". Cell. 163 (3): 712–23. doi:10.1016/j.cell.2015.09.053. PMID 26496610.
  6. ^ a b Ninagawa S, Okada T, Sumitomo Y, Horimoto S, Sugimoto T, Ishikawa T, Takeda S, Yamamoto T, Suzuki T, Kamiya Y, Kato K, Mori K (November 2015). "Forcible destruction of severely misfolded mammalian glycoproteins by the non-glycoprotein ERAD pathway". The Journal of Cell Biology. 211 (4): 775–84. doi:10.1083/jcb.201504109. PMC 4657166. PMID 26572623.
  7. ^ a b Kopec KO, Lupas AN (15 October 2013). "β-Propeller blades as ancestral peptides in protein evolution". PLOS ONE. 8 (10): e77074. Bibcode:2013PLoSO...877074K. doi:10.1371/journal.pone.0077074. PMC 3797127. PMID 24143202.
  8. ^ Ghosh M, Anthony C, Harlos K, Goodwin MG, Blake C (February 1995). "The refined structure of the quinoprotein methanol dehydrogenase from Methylobacterium extorquens at 1.94 A". Structure. 3 (2): 177–87. doi:10.1016/s0969-2126(01)00148-4. PMID 7735834.
  9. ^ Goebl M, Yanagida M (May 1991). "The TPR snap helix: a novel protein repeat motif from mitosis to transcription". Trends in Biochemical Sciences. 16 (5): 173–7. doi:10.1016/0968-0004(91)90070-c. PMID 1882418.
  10. ^ Lamb JR, Tugendreich S, Hieter P (July 1995). "Tetratrico peptide repeat interactions: to TPR or not to TPR?". Trends in Biochemical Sciences. 20 (7): 257–9. doi:10.1016/s0968-0004(00)89037-4. PMID 7667876.
  11. ^ Das AK, Cohen PW, Barford D (March 1998). "The structure of the tetratricopeptide repeats of protein phosphatase 5: implications for TPR-mediated protein-protein interactions". The EMBO Journal. 17 (5): 1192–9. doi:10.1093/emboj/17.5.1192. PMC 1170467. PMID 9482716.
  12. ^ Mitra M, Melis A (February 2010). "Genetic and biochemical analysis of the TLA1 gene in Chlamydomonas reinhardtii". Planta. 231 (3): 729–40. doi:10.1007/s00425-009-1083-3. PMC 2806527. PMID 20012986.
  13. ^ Mitra M, Kirst H, Dewez D, Melis A (December 2012). "Modulation of the light-harvesting chlorophyll antenna size in Chlamydomonas reinhardtii by TLA1 gene over-expression and RNA interference". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 367 (1608): 3430–43. doi:10.1098/rstb.2012.0229. PMC 3497077. PMID 23148270.
  14. ^ Dunkley TP, Hester S, Shadforth IP, Runions J, Weimar T, Hanton SL, Griffin JL, Bessant C, Brandizzi F, Hawes C, Watson RB, Dupree P, Lilley KS (April 2006). "Mapping the Arabidopsis organelle proteome". Proceedings of the National Academy of Sciences of the United States of America. 103 (17): 6518–23. Bibcode:2006PNAS..103.6518D. doi:10.1073/pnas.0506958103. PMC 1458916. PMID 16618929.
  15. ^ a b Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL (March 2013). "Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex". Proceedings of the National Academy of Sciences of the United States of America. 110 (11): E1055–63. doi:10.1073/pnas.1216154110. PMC 3600456. PMID 23431131.
  16. ^ a b Satoh T, Ohba A, Liu Z, Inagaki T, Satoh AK (February 2015). "dPob/EMC is essential for biosynthesis of rhodopsin and other multi-pass membrane proteins in Drosophila photoreceptors". eLife. 4. doi:10.7554/eLife.06306. PMC 4341237. PMID 25715730.
  17. ^ a b Li Y, Zhao Y, Hu J, Xiao J, Qu L, Wang Z, Ma D, Chen Y (February 2013). "A novel ER-localized transmembrane protein, EMC6, interacts with RAB5A and regulates cell autophagy". Autophagy. 9 (2): 150–63. doi:10.4161/auto.22742. PMC 3552880. PMID 23182941.
  18. ^ a b c Shen X, Kan S, Hu J, Li M, Lu G, Zhang M, Zhang S, Hou Y, Chen Y, Bai Y (January 2016). "EMC6/TMEM93 suppresses glioblastoma proliferation by modulating autophagy". Cell Death & Disease. 7 (1): e2043. doi:10.1038/cddis.2015.408. PMC 4816184. PMID 26775697.
  19. ^ Raj S, Krishnan K, Askew DS, Helynck O, Suzanne P, Lesnard A, Rault S, Zeidler U, d'Enfert C, Latgé JP, Munier-Lehmann H, Saveanu C (December 2015). "The Toxicity of a Novel Antifungal Compound Is Modulated by Endoplasmic Reticulum-Associated Protein Degradation Components". Antimicrobial Agents and Chemotherapy. 60 (3): 1438–49. doi:10.1128/aac.02239-15. PMC 4775935. PMID 26666917.
  20. ^ a b c Ma H, Dang Y, Wu Y, Jia G, Anaya E, Zhang J, Abraham S, Choi JG, Shi G, Qi L, Manjunath N, Wu H (July 2015). "A CRISPR-Based Screen Identifies Genes Essential for West-Nile-Virus-Induced Cell Death". Cell Reports. 12 (4): 673–83. doi:10.1016/j.celrep.2015.06.049. PMC 4559080. PMID 26190106.
  21. ^ Chitwood, Patrick J.; Juszkiewicz, Szymon; Guna, Alina; Shao, Sichen; Hegde, Ramanujan S. (2018-11-29). "EMC Is Required to Initiate Accurate Membrane Protein Topogenesis". Cell. 175 (6): 1507–1519.e16. doi:10.1016/j.cell.2018.10.009. ISSN 1097-4172. PMC 6269167. PMID 30415835.
  22. ^ Shurtleff, Matthew J.; Itzhak, Daniel N.; Hussmann, Jeffrey A.; Schirle Oakdale, Nicole T.; Costa, Elizabeth A.; Jonikas, Martin; Weibezahn, Jimena; Popova, Katerina D.; Jan, Calvin H. (May 29, 2018). "The ER membrane protein complex interacts cotranslationally to enable biogenesis of multipass membrane proteins". eLife. 7. doi:10.7554/eLife.37018. ISSN 2050-084X. PMC 5995541. PMID 29809151.
  23. ^ Volkmar, Norbert; Thezenas, Maria-Laetitia; Louie, Sharon M.; Juszkiewicz, Szymon; Nomura, Daniel K.; Hegde, Ramanujan S.; Kessler, Benedikt M.; Christianson, John C. (2019-01-16). "The ER membrane protein complex promotes biogenesis of sterol-related enzymes maintaining cholesterol homeostasis". Journal of Cell Science. 132 (2): jcs223453. doi:10.1242/jcs.223453. ISSN 1477-9137. PMC 6362398. PMID 30578317.
  24. ^ a b Guna A, Volkmar N, Christianson JC, Hegde RS (January 2018). "The ER membrane protein complex is a transmembrane domain insertase". Science. 359 (6374): 470–473. Bibcode:2018Sci...359..470G. doi:10.1126/science.aao3099. PMC 5788257. PMID 29242231.
  25. ^ Louie RJ, Guo J, Rodgers JW, White R, Shah N, Pagant S, Kim P, Livstone M, Dolinski K, McKinney BA, Hong J, Sorscher EJ, Bryan J, Miller EA, Hartman JL (December 2012). "A yeast phenomic model for the gene interaction network modulating CFTR-ΔF508 protein biogenesis". Genome Medicine. 4 (12): 103. doi:10.1186/gm404. PMC 3906889. PMID 23270647.
  26. ^ Bircham PW, Maass DR, Roberts CA, Kiew PY, Low YS, Yegambaram M, Matthews J, Jack CA, Atkinson PH (September 2011). "Secretory pathway genes assessed by high-throughput microscopy and synthetic genetic array analysis". Molecular BioSystems. 7 (9): 2589–98. doi:10.1039/c1mb05175j. PMID 21731954.
  27. ^ Chen, Zhou; Mondal, Abhisek; Abderemane-Ali, Fayal; Jang, Seil; Niranjan, Sangeeta; Montaño, José L.; Zaro, Balyn W.; Minor, Daniel L. (July 2023). "EMC chaperone–CaV structure reveals an ion channel assembly intermediate". Nature. 619 (7969): 410–419. Bibcode:2023Natur.619..410C. doi:10.1038/s41586-023-06175-5. PMC 10896479. PMID 37196677. S2CID 258763550.
  28. ^ a b 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.
  29. ^ Vance JE (May 1990). "Phospholipid synthesis in a membrane fraction associated with mitochondria". The Journal of Biological Chemistry. 265 (13): 7248–56. doi:10.1016/S0021-9258(19)39106-9. PMID 2332429.
  30. ^ Vance, J. E. (1991-01-05). "Newly made phosphatidylserine and phosphatidylethanolamine are preferentially translocated between rat liver mitochondria and endoplasmic reticulum". The Journal of Biological Chemistry. 266 (1): 89–97. doi:10.1016/S0021-9258(18)52406-6. ISSN 0021-9258. PMID 1898727.
  31. ^ Savidis G, McDougall WM, Meraner P, Perreira JM, Portmann JM, Trincucci G, John SP, Aker AM, Renzette N, Robbins DR, Guo Z, Green S, Kowalik TF, Brass AL (June 2016). "Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics". Cell Reports. 16 (1): 232–246. doi:10.1016/j.celrep.2016.06.028. PMID 27342126.
  32. ^ Junes-Gill KS, Gallaher TK, Gluzman-Poltorak Z, Miller JD, Wheeler CJ, Fan X, Basile LA (April 2011). "hHSS1: a novel secreted factor and suppressor of glioma growth located at chromosome 19q13.33". Journal of Neuro-Oncology. 102 (2): 197–211. doi:10.1007/s11060-010-0314-6. PMC 3052511. PMID 20680400.
  33. ^ Harel T, Yesil G, Bayram Y, Coban-Akdemir Z, Charng WL, Karaca E, Al Asmari A, Eldomery MK, Hunter JV, Jhangiani SN, Rosenfeld JA, Pehlivan D, El-Hattab AW, Saleh MA, LeDuc CA, Muzny D, Boerwinkle E, Gibbs RA, Chung WK, Yang Y, Belmont JW, Lupski JR (March 2016). "Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy". American Journal of Human Genetics. 98 (3): 562–570. doi:10.1016/j.ajhg.2016.01.011. PMC 4800043. PMID 26942288.
  34. ^ Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS (February 2013). "Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes". Genome Research. 23 (2): 236–47. doi:10.1101/gr.144105.112. PMC 3561865. PMID 23105016.
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