The Structure of the Membrane Protein of SARS-CoV-2 Resembles the Sugar Transporter SemiSWEET
Article Sidebar
Main Article Content
Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the disease COVID-19 that has decimated the health and economy of our planet. The virus causes the disease not only in people but also in companion and wild animals. People with diabetes are at risk of the disease. As yet we do not know why the virus has been highly successful in causing the pandemic within 3 months of its first report. The structural proteins of SARS include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S).
Methods: The structure and function of the most abundant structural protein of SARS-CoV-2, the membrane (M) glycoprotein, is not fully understood. Using in silico analyses we determined the structure and potential function of the M protein.
Results: The M protein of SARS-CoV-2 is 98.6% similar to the M protein of bat SARS-CoV, maintains 98.2% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only 38% with the M protein of MERS-CoV. In silico analyses showed that the M protein of SARS-CoV-2 has a triple helix bundle, forms a single 3-transmembrane domain, and is homologous to the prokaryotic sugar transport protein SemiSWEET. SemiSWEETs are related to the PQ-loop family whose members function as cargo receptors in vesicle transport, mediate movement of basic amino acids across lysosomal membranes, and are also involved in phospholipase flippase function.
Conclusions: The advantage and role of the M protein having a sugar transporter-like structure is not clearly understood. The M protein of SARS-CoV-2 interacts with S, E, and N protein. The S protein of the virus is glycosylated. It could be hypothesized that the sugar transporter-like structure of the M protein influences glycosylation of the S protein. Endocytosis is critical for the internalization and maturation of RNA viruses, including SARS-CoV-2. Sucrose is involved in endosome and lysosome maturation and may also induce autophagy, pathways that help in the entry of the virus. Overall, it could be hypothesized that the SemiSWEET sugar transporter-like structure of the M protein may be involved in multiple functions that may aid in the rapid proliferation, replication, and immune evasion of the SARS-CoV-2 virus. Biological experiments would validate the presence and function of the SemiSWEET sugar transporter.
Downloads
Article Details
Pathogens and Immunity abides by Creative Commons BY 4.0:
http://creativecommons.org/licenses/by/4.0/
This license lets others distribute, remix, tweak, and build upon your work for any lawful purpose, even commercially, as long as they credit you for the original creation. This is the most accommodating of licenses offered. Recommended for maximum dissemination and use of licensed materials. The authors maintain copyright of their materal.
*Due to a template error on our pdfs, articles published from May 20, 2016 to June 24, 2022 incorrectly state the copyright is held by Pathogens and Immunity. Copyright of all articles is held by the authors of each article as noted in the above copyright policy.
References
1. Yang X, Zhao J, Yan Q, Zhang S, Wang Y, Li Y. A case of COVID-19 patient with the diarrhea as initial symptom and literature review. Clin Res Hepatol Gastroenterol 2020; pii: S2210-7401(20)30085-1. DOI: 10.1016/j.clinre.2020.03.013.
2. Effenberger M, Grabherr F, Mayr L, Schwaerzler J, Nairz M, Seifert M, Hilbe R, Seiwald S, Scholl-Buergi S, Fritsche G, Bellmann-Weiler R, Weiss G, Müller T, Adolph TE, Tilg H. Faecal calprotectin indicates intestinal inflammation in COVID-19. Gut 2020; pii: gutjnl-2020-321388. DOI: 10.1136/gutjnl-2020-321388.
3. Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M. Presumed asymptomatic carrier transmission of COVID-19. JAMA 2020; 323:1406-1407. DOI: 10.1001/jama.2020.2565.
4. Gao Z, Xu Y, Sun C, et al. A systematic review of asymptomatic infections with COVID-19. J Microbiol Immunol Infect 2020; (in press). DOI: 10.1016/j.jmii.2020.05.001.
5. Wang X, Xu W, Hu G, Xia S, Sun Z, Liu Z, Xie Y, Zhang R, Jiang S, Lu L. SARS-CoV-2 infects T lymphocytes through its spike protein-mediated membrane fusion. Cell Mol Immunol 2020; (in press). DOI: 10.1038/s41423-020-0424-9.
6. Shereen MA, Khan S, Kazmi A, Bashir N, Siddique R. COVID-19 infection: Origin, transmission, and characteristics of human coronaviruses. J Adv Res 2020; 24:91-98. DOI: 10.1016/j.jare.2020.03.005.
7. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, Yuen KY. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect 2020; 9:221-236. DOI: 10.1080/22221751.2020.1719902.
8. Wrapp D, Wang N, Corbett KS, Goldsmith JA, Hsieh C-L, Abiona O, Graham BS, McLellan JS. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 2020; 367: 1260–1263.
9. Amraie R, Napoleon MA, Yin W, et al. CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2 and are differentially expressed in lung and kidney epithelial and endothelial cells. Preprint. bioRxiv 2020;2020.06.22.165803. DOI: 10.1101/2020.06.22.165803.
10. Mousavizadeh L, Ghasemi S. Genotype and phenotype of COVID-19: Their roles in pathogenesis. J Microbiol Immunol Infect 2020; pii: S1684-1182(20)30082-7.
11. Astuti I, Ysrafil. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): An overview of viral structure and host response. Diabetes Metab Syndr 2020; 14:407-412. DOI: 10.1016/j.dsx.2020.04.020.
12. Bianchi M, Benvenuto D, Giovanetti M, Angeletti S, Ciccozzi M, Pascarella S. Sars-CoV-2 envelope and membrane proteins: Structural differences linked to virus characteristics? Biomed Res Int 2020; 2020:4389089. DOI: 10.1155/2020/4389089.
13. Watanabe, Y., Berndsen, Z.T., Raghwani, J. et al. Vulnerabilities in coronavirus glycan shields despite extensive glycosylation. Nat Commun 2020a; 11, 2688.
14. Watanabe Y, Allen JD, Wrapp D, McLellan JS, Crispin M. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 2020b; 369: 330-333.
15. Chen LQ, Hou BH, Lalonde S, Takanaga H, Hartung ML, Qu XQ, Guo WJ, Kim JG, Underwood W, Chaudhuri B, Chermak D, Antony G, White FF, Somerville SC, Mudgett MB, Frommer WB. Sugar transporters for intercellular exchange and nutrition of pathogens. Nature 2010; 468:527-532. DOI: 10.1038/nature09606.
16. Feng L, Frommer WB. Structure and function of semiSWEET and SWEET sugar transporters. Trends Biochem Sci 2015; 40: 480-486. DOI: 10.1016/j.tibs.2015.05.005.
17. Jia B, Hao L, Xuan YH, Jeon CO. New insight into the diversity of semiSWEET sugar transporters and the homologs in prokaryotes. Front Genet 2018; 9:180. DOI: 10.3389/fgene.2018.00180.
18. Jeena GS, Kumar S, Shukla RK. Structure, evolution and diverse physiological roles of SWEET sugar transporters in plants. Plant Mol Biol 2019; 100:351-365. DOI: 10.1007/s11103-019-00872-4.
19. Chen LQ. SWEET sugar transporters for phloem transport and pathogen nutrition. New Phytol 2014; 201:1150-1155. DOI: 10.1111/nph.12445.
20. Han L, Zhu Y, Liu M, Zhou Y, Lu G, Lan L, Wang X, Zhao Y, Zhang XC. Molecular mechanisms of substrate recognition and transport by the AtSWEET 13 sugar transporter. Proc Natl Acad Sci USA 2017; 114:10089-10094. DOI: 10.1073/pnas.1709241114.
21. Xuan YH, Hu YB, Chen LQ, Sosso D, Ducat DC, Hou BH, Frommer WB. Functional role of oligomerization for bacterial and plant SWEET sugar transporter family. Proc Natl Acad Sci USA 2013; 110: E3685-94. DOI: 10.1073/pnas.1311244110.
22. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, Heer FT, de Beer TAP, Rempfer C, Bordoli L, Lepore R, Schwede T. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res 2018; 46(W1):W296-W303. DOI: 10.1093/nar/gky427.
23. Skrabanek L, Campagne F, Weinstein H. Building protein diagrams on the web with the residue-based diagram editor RbDe. Nucleic Acids Res 2003; 31: 3856-3858. DOI: 10.1093/nar/gkg552.
24. Omasits U, Ahrens CH, Müller S, Wollscheid B. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics 2014; 30:884-6. DOI: 10.1093/bioinformatics/btt607.
25. Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994; 22:4673-80. DOI: 10.1093/nar/22.22.4673.
26. Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: An automated protein homology-modeling server. Nucleic Acids Res 2003; 31: 3381-3385. DOI: 10.1093/nar/gkg520.
27. Ghosh AK, Brindisi M, Shahabi D, Chapman ME, Mesecar AD. Drug development and medicinal chemistry efforts toward SARS-Coronavirus and Covid-19 therapeutics. Chem Med Chem 2020; 15: 907-932. DOI: 10.1002/cmdc.202000223.
28. Castagnoli R, Votto M, Licari A, Brambilla I, Bruno R, Perlini S, Rovida F, Baldanti F, Marseglia GL. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in children and adolescents: A systematic review. JAMA Pediatr 2020; (in press). DOI: 10.1001/jamapediatrics.2020.1467.
29. Ngonghala CN, Iboi E, Eikenberry S, Scotch M, MacIntyre CR, Bonds MH, Gumel AB. Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing the 2019 novel Coronavirus. Math Biosci 2020; 325: 108364. DOI: 10.1016/j.mbs.2020.108364.
30. Howard J, Huang A, Li Z, Tufekci Z, Zdimal V, van der Westhuizen H, von Delft A, Price A, Fridman L, Tang L, Tang V, Watson GL, Bax CE, Shaikh R, Questier F, Hernandez D, Chu LF, Ramirez CM, Rimoin AW. Face masks against COVID-19: An evidence review. Preprints 2020, 2020040203. DOI: 10.20944/preprints202004.0203.v3.
31. Jayaweera M, Perera H, Gunawardana B, Manatunge J. Transmission of COVID-19 virus by droplets and aerosols: A critical review on the unresolved dichotomy. Environ Res 2020; 188:109819. DOI: 10.1016/j.envres.2020.109819.
32. Bahl P, Doolan C, de Silva C, Chughtai AA, Bourouiba L, MacIntyre CR. Airborne or droplet precautions for health workers treating COVID-19? J Infect Dis 2020 Apr 16: jiaa189. DOI: 10.1093/infdis/jiaa189.
33. Eikenberry SE, Mancuso M, Iboi E, Phan T, Eikenberry K, Kuang Y, Kostelich E, Gumel AB. To mask or not to mask: Modeling the potential for face mask use by the general public to curtail the COVID-19 pandemic. Infect Dis Model 2020; 5: 293–308. DOI: 10.1016/j.idm.2020.04.001.
34. Chu DK, Akl EA, Duda S, Solo K, Yaacoub S, Schünemann HJ; COVID-19 Systematic Urgent Review Group Effort (SURGE) study authors. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 2020; 395: 1973-1987. DOI: 10.1016/S0140-6736(20)31142-9.
35. Le T, Andreadakis Z, Kumar A, Gómez Román R, Tollefsen S, Saville M, Mayhew S. The COVID-19 vaccine development landscape. Nat Rev Drug Discov 2020; 19:305-306.
36. Liu YM, Shahed-Al-Mahmud M, Chen X, et al. A carbohydrate-binding protein from the edible Lablab beans effectively blocks the infections of influenza viruses and SARS-CoV-2. Cell Rep 2020; 32:108016. DOI: 10.1016/j.celrep.2020.108016.
37. Thaker SK, Ch’ng J, Christofk HR. Viral hijacking of cellular metabolism. BMC Biol 2019; 17:59. DOI: 10.1186/s12915-019-0678-9.
38. Deng D, Yan N. GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters. Protein Sci 2016; 25: 546-558. DOI: 10.1002/pro.2858.
39. Bezrutczyk M, Yang J, Eom JS, Prior M, Sosso D, Hartwig T, Szurek B, Oliva R, Vera-Cruz C, White FF, Yang B, Frommer WB. Sugar flux and signaling in plant-microbe interactions. Plant J 2018; 93:675-685. DOI: 10.1111/tpj.13775.
40. Chen LQ, Cheung LS, Feng L, Tanner W, Frommer WB. Transport of sugars. Annu Rev Biochem 2015; 84: 865–894. DOI: 10.1146/annurev-biochem-060614-033904.
41. Lee Y, Nishizawa T, Yamashita K, Ishitani R, Nureki O. Structural basis for the facilitative diffusion mechanism by SemiSWEET transporter. Nat Commun 2015; 6:6112. DOI: 10.1038/ncomms7112.
42. Saudek V. Cystinosin, MPDU1, SWEETs and KDELR belong to a well-defined protein family with putative function of cargo receptors involved in vesicle trafficking. PLoS One. 2012; 7(2):e30876. DOI: 10.1371/journal.pone.0030876.
43. Yamamoto T, Fujimura-Kamada, K, Shioji E, Suzuki R, Tanaka K. Cfs1p, a novel membrane protein in the PQ-loop family, is involved in phospholipid flippase functions in Yeast. G3 2017; 7: 179–192. DOI: 10.1534/g3.116.035238.
44. Kawano-Kawada M, Manabe K, Ichimura H, Kimura T, Harada Y, Ikeda K, Tanaka S, Kakinuma Y, Sekito T. A PQ-loop protein Ypq2 is involved in the exchange of arginine and histidine across the vacuolar membrane of Saccharomyces cerevisiae. Sci Rep 2019; 9:15018. DOI: 10.1038/s41598-019-51531-z.
45. Bornstein SR, Rubino F. et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol 2020; 8: 546-550. DOI: 10.1016/S2213-8587(20)30152-2.
46. Iacobellis G, Penaherrera CA, Bermudez LE, Bernal Mizrachi E. Admission hyperglycemia and radiological findings of SARS-CoV2 in patients with and without diabetes. Diabetes Res Clin Pract 2020; 164:108185. DOI: 10.1016/j.diabres.2020.108185.
47. Wu Z, McGoogan JM. Characteristics of and important lessons from the coronavirus disease 2019 (COVID-19) outbreak in China: Summary of a report of 72 314 cases from the Chinese Center for Disease Control and Prevention. JAMA 2020; 323:1239–1242. DOI: 10.1001/jama.2020.2648.
48. Yang JK, Lin SS, Ji XJ, Guo LM. Binding of SARS coronavirus to its receptor damages islets and causes acute diabetes. Acta Diabetol 2010; 47:193-199. DOI: 10.1007/s00592-009-0109-4.
49. Badawi A, Ryoo SG. Prevalence of comorbidities in the Middle East respiratory syndrome coronavirus (MERS-CoV): a systematic review and meta-analysis. Int J Infect Dis 2016; 49:129-33. DOI: 10.1016/j.ijid.2016.06.015.
50. Nassar MS, Bakhrebah MA, Meo SA, Alsuabeyl MS, Zaher WA. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) infection: epidemiology, pathogenesis and clinical characteristics. Eur Rev Med Pharmacol Sci 2018; 22:4956-4961. DOI: 10.26355/eurrev_201808_15635.
51. Bassendine MF, Bridge SH, McCaughan GW, Gorrell MD. COVID-19 and comorbidities: A role for dipeptidyl peptidase 4 (DPP4) in disease severity? J. Diabetes 2020;10.1111/1753-0407.13052. DOI: 10.1111/1753-0407.13052.
52. Rhee SY, Lee J, Nam H, Kyoung D-S, Kim DJ. Effects of a DPP-4 inhibitor and RAS blockade on clinical outcomes of patients with diabetes and COVID-19. medRxiv 2020.05.20.20108555. DOI: 10.1101/2020.05.20.20108555.
53. Yu Y, Clippinger AJ, Pierciey FJ Jr, Alwine JC. Viruses and metabolism: alterations of glucose and glutamine metabolism mediated by human cytomegalovirus. Adv Virus Res 2011; 80:49-67. DOI: 10.1016/B978-0-12-385987-7.00003-8.
54. Dai L, Hu WW, Xia L, Xia M, Yang Q. Transmissible gastroenteritis virus infection enhances SGLT1 and GLUT2 expression to increase glucose uptake. PLoS One 2016; 11(11):e0165585. DOI: 10.1371/journal.pone.0165585.
55. Gualdoni GA, Mayer KA, Kapsch AM, Kreuzberg K, Puck A, Kienzl P, Oberndorfer F, Frühwirth K, Winkler S, Blaas D, Zlabinger GJ, Stöckl J. Rhinovirus induces an anabolic reprogramming in host cell metabolism essential for viral replication. Proc Natl Acad Sci USA 2018; 115: E7158-E7165. DOI: 10.1073/pnas.1800525115.
56. Higuchi T, Nishikawa J, Inoue H. Sucrose induces vesicle accumulation and autophagy. J Cell Biochem 2015; 116: 609-617. DOI: 10.1002/jcb.25012.
57. Zhao YG, Zhang H. Autophagosome maturation: An epic journey from the ER to lysosomes. J Cell Biol 2019; 218: 757-770. DOI: 10.1083/jcb.201810099.
58. Burkard C, Verheije MH, Wicht O, van Kasteren SI, van Kuppeveld FJ, Haagmans BL, Pelkmans L, Rottier PJ, Bosch BJ, de Haan CA. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner. PLoS Pathog 2014; 10(11):e1004502. DOI: 10.1371/journal.ppat.1004502.
59. Yang N, Shen HM. Targeting the endocytic pathway and autophagy process as a novel therapeutic strategy in COVID-19. Int J Biol Sci 2020; 16:1724-1731. DOI: 10.7150/ijbs.45498.
60. de Haan CA, Smeets M, Vernooij F, Vennema H, Rottier PJ. Mapping of the coronavirus membrane protein domains involved in interaction with the spike protein. J Virol 1999; 73: 7441-7452.
61. Zhang T, Wu Q, Zhang Z. Probable pangolin origin of SARS-CoV-2 associated with the COVID-19 outbreak. Curr Biol 2020; 30:1346-1351.e2. DOI: 10.1016/j.cub.2020.03.022.
62. White JM, Whittaker GR. Fusion of enveloped viruses in endosomes. Traffic 2016; 17: 593-614. DOI: 10.1111/tra.12389.
63. Yap SSL, Nguyen-Khuong T, Rudd PM, Alonso S. Dengue virus glycosylation: What do we know? Front Microbiol 2017; 8:1415. DOI: 10.3389/fmicb.2017.01415.
64. Caffaro CE, Koshy AA, Liu L, Zeiner GM, Hirschberg CB, Boothroyd JC. A nucleotide sugar transporter involved in glycosylation of the Toxoplasma tissue cyst wall is required for efficient persistence of bradyzoites. PLoS Pathog 2013; 9(5): e1003331. DOI: 10.1371/journal.ppat.1003331.
65. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18: 844-847. DOI: 10.1111/jth.14768.
66. Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18: 1094-1099. DOI: 10.1111/jth.14817.
67. Fidler TP, Campbell RA, Funari T, Dunne N, Balderas Angeles E, Middleton EA, Chaudhuri D, Weyrich AS, Abel ED. Deletion of GLUT1 and GLUT3 reveals multiple roles for glucose metabolism in platelet and megakaryocyte function. Cell Rep 2017; 21:1705. DOI: 10.1016/j.celrep.2017.06.083.
68. Fidler TP, Marti A, Gerth K, Middleton EA, Campbell RA, Rondina MT, Weyrich AS, Abel ED. Glucose metabolism is required for platelet hyperactivation in a murine model of type 1 diabetes. Diabetes 2019; 68: 932-938. DOI: 10.2337/db18-0981.
69. Zhang JZ, Behrooz A, Ismail-Beigi F. Regulation of glucose transport by hypoxia. Am. J Kidney Dis 1999; 34: 189-202. DOI: 10.1016/s0272-6386(99)70131-9.
70. Wood IS, Wang B, Lorente-Cebrián S, Trayhurn P. Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes. Biochem Biophys Res Commun 2007; 361: 468-73. DOI: 10.1016/j.bbrc.2007.07.032.
71. Ouiddir A, Planès C, Fernandes I, VanHesse A, Clerici C. Hypoxia upregulates activity and expression of the glucose transporter GLUT1 in alveolar epithelial cells. Am. J. Respir. Cell Mol Biol 1999; 21: 710-718. DOI: 10.1165/ajrcmb.21.6.3751.
72. Sadlecki P, Bodnar M, Grabiec M, Marszalek A, Walentowicz P, Sokup A, Zegarska J, Walentowicz-Sadlecka M. The role of Hypoxia-inducible factor-1 α, glucose transporter-1, (GLUT-1) and carbon anhydrase IX in endometrial cancer patients. Biomed Res Int 2014; 2014:616850. DOI: 10.1155/2014/616850.
73. Eckle T, Brodsky K, Bonney M, Packard T, Han J, Borchers CH, et al. (2013) HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium. PLoS Biol 11(9): e1001665. DOI: 10.1371/journal.pbio.1001665.
74. Merigo F, Benati D, Cristofoletti M, Osculati F, Sbarbati A. Glucose transporters are expressed in taste receptor cells. J Anat 2011; 219:243-252. DOI: 10.1111/j.1469-7580.2011.01385.x.
75. Al Koborssy D, Palouzier-Paulignan B, Salem R, Thevenet M, Romestaing C, Julliard AK. Cellular and molecular cues of glucose sensing in the rat olfactory bulb. Front Neurosci 2014; 8:333. DOI: 10.3389/fnins.2014.00333.
76. Villar PS, Delgado R, Vergara C, Reyes JG, Bacigalupo J. Energy requirements of odor transduction in the chemosensory cilia of olfactory sensory neurons rely on oxidative phosphorylation and glycolytic processing of extracellular glucose. J Neurosci 2017; 37: 5736-5743. DOI: 10.1523/JNEUROSCI.2640-16.2017.