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DOI: 10.56871/RBR.2024.11.95.006
УДК 578.834.1+616-036.21+577.217+577.112+577.322.7+547.96
БЕЛКИ SARS CoV-2 И БЕЛКИ ЧЕЛОВЕЧЕСКОГО ОРГАНИЗМА
© Александр Тимурович Марьянович1, Дмитрий Юрьевич Кормилец2
1 Северо-Западный государственный медицинский университет им. И.И. Мечникова. 195067, Российская Федерация, г. Санкт-Петербург, Пискаревский пр., 47
2 Военно-медицинская академия им. С.М. Кирова. 194044, Российская Федерация, г. Санкт-Петербург, ул. Академика Лебедева, 6
Контактная информация: Александр Тимурович Марьянович — д.б.н., профессор, заведующий кафедрой нормальной физиологии. E-mail: [email protected] ORCID: https://orcid.org/0000-0001-7482-3403 SPIN: 5957-2347
Для цитирования: Марьянович А.Т., Кормилец Д.Ю. Белки SARS CoV-2 и белки человеческого организма // Российские биомедицинские исследования. 2024. Т. 9. № 1. С. 48-58. DOI: https://doi.org/10.56871/RBR.2024.11.95.006
Поступила: 21.11.2023 Одобрена: 08.01.2024 Принята к печати: 04.03.2024
Резюме. Белки SARS CoV-2 представляют собой молекулы с массой от нескольких десятков до нескольких тысяч аминокислотных остатков. Существуют структурные и неструктурные белки. К первым относятся шиповый гликопротеин, или S-белок (S), малый мембранный оболочечный белок (E), мембранный белок (M) и нуклеопротеин или нуклеокапсид (N). Вторая группа состоит из 16 неструктурных белков (Nsp1-16, включая полипротеины репликазы RPP 1a и lab) и 10 вспомогательных факторов или белков открытой рамки считывания (ORF3a, 3b, 6, 7a, 7b, 8, 9b, 9c, 10 и 14). Белки S, E и M, расположенные снаружи и в мембране вириона, участвуют в контакте вириона с клеткой и проникновении в нее. Другие белки участвуют в захвате внутриклеточных механизмов и их использовании в собственных интересах вируса. Большинство этих белков содержат многочисленные мотивы, гомологичные человеческим белкам, в том числе таким важным, как интерлейкин-7. Возможно, эта гомология является важным фактором, позволяющим «обмануть» иммунную систему на начальных стадиях инфекции и спровоцировать аутоиммунный ответ впоследствии. Гомология белков SARS CoV-2, с одной стороны, и белков вкусовых и обонятельных рецепторов — с другой, возможно, объясняет причины нарушения восприятия вкусовых и обонятельных раздражителей, характерного для COVID-инфекции.
Ключевые слова: COVID-19, SARS CoV-2, гомология белка, рецептор-связывающий домен, интерлейкин-7, рецептор ACE2, врожденный иммунитет, аутоиммунитет, обоняние, вкус
SARS CoV-2 PROTEINS AND HUMAN PROTEINS
© Alexander T. Maryanovich1, Dmitry Yu. Kormilets2
1 North-Western State Medical University named after I.I. Mechnikov. Piskarevskiy ave., 47, Saint Petersburg, Russian Federation, 195067
2 Military Medical Academy named after S.M. Kirov. Akademician Lebedev str., 6, Saint Petersburg, Russian Federation, 194044
Contact information: Alexander T. Maryanovich — PhD, D.Sc. (Biology), Professor, Head of Department of Physiology. E-mail: [email protected] ORCID: https://orcid.org/0000-0001-7482-3403 SPIN: 5957-2347
For citation: Maryanovich AT, Kormilets DYu. SARS CoV-2 proteins and human proteins. Russian Biomedical Research. 2024;9(1):48-58. DOI: https://doi. org/10.56871/RBR.2024.11.95.006
Received: 21.11.2023 Revised: 08.01.2024 Accepted: 04.03.2024
Abstract. SARS CoV-2 proteins are molecules with a mass of several tens to several thousand amino acid residues. There are structural and nonstructural proteins. The former include Spike glycoprotein (S), small membrane envelope protein (E), membrane protein (M), and nucleoprotein or nucleocapsid (N). The second group consists of 16 nonstructural proteins (Nsp1-16, including replicase polyproteins RPP 1a and 1ab) and 10 accessory factors or open reading frame
proteins (ORF3a, 3b, 6, 7a, 7b, 8, 9b, 9c, 10 and 14). Proteins S, E and M, located outside and in the membrane of a virion, are involved in the contact of the virion with a cell and penetration into it. Other proteins are involved in the hijacking of intracellular mechanisms and their use in the virus's own interests. Most of these proteins contain numerous motifs that are homologous to human proteins including such important ones as Interleukin-7. Perhaps this homology is an important factor in deceiving the immune system at the initial stages of infection and provoking an autoimmune response later. The homology of SARS CoV-2 proteins on the one hand and taste and olfactory receptor proteins on the other hand may possibly explain the causes of the impaired perception of taste and olfactory stimuli characteristic of COVID infection.
Keywords: COVID-19, SARS CoV-2, protein homology, receptor-binding domain, interleukin-7, ACE2 receptor, congenital innunity, autoimmunity, sense of smell, sense of taste
INTRODUCTION
Why is the new SARS CoV-2 coronavirus so infectious? Why many cases of COVID-19 infection are so severe? Why many patients are reported with complete loss of smell and taste? Answers to these questions should be received as soon as possible. The COVID-19 pandemic, which has plagued humanity for almost two years now, does not allow us to follow the usual course of encyclopedia authors: wait, carefully sift through ideas and facts, and wait for new ones to come. In this case (which should not become a precedent), one has to pay attention not only to firmly established experimental data, but also to some hypotheses.
The study of the proteome of the original ("canonical" or Wuhan) variant of SARS CoV-2 proceeds in two directions. Using 3D models, the researchers can determine how the spike protein binds to the ACE2 receptor [1]. This knowledge will help in creating binding blockers.
The alignment method compares the primary structures of millions of proteins [2]. The method allows you to detect the homology of SARS CoV-2 proteins with proteins of humans and other organisms [3]. Probably, the information on homology makes it possible to understand the mechanisms of the virus bypassing the innate immunity system (evasion) at the early stages of the development of the infectious process and the process of provoking an autoimmune response at later stages.
The issue of mutations in SARS CoV-2, and especially of its S protein, is becoming increasingly important. With the help of mutations, the virus "learns" to avoid immune responses [4].
Table 1
SARS CoV-2 proteins: structural and nonstructural
Group Proteins
Structural Spike glycoprotein, S Envelope small membrane protein, E Membrane protein, M Nucleoprotein, N
Nonstructural ORF3a, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORFIO, ORF14, RPP 1a, RPP 1ab
ORF, open reading frame. RPP, Replicase polyprotein.
SARS CoV-2 proteins vary significantly in length — from several tens to several thousands amino acid residues. They are traditionally divided into structural and nonstructural (Table 1).
STRUCTURAL PROTEINS
Spike glycoprotein
Spike (S) protein molecule consists of 1273 amino acid residues:
MFVFLVLLPLVSSQCVNLTTRTQLPPAYTNSFTRGVYYPDK VFRSSVLHSTQDLFLPFFSNVTWFHAIHVSGTNGTKRFDN PVLPFNDGVYFASTEKSNIIRGWIFGTTLDSKTQSLLIVNNA TNVVIKVCEFQFCNDPFLGVYYHKNNKSWMESEFRVYSS ANNCTFEYVSQPFLMDLEGKQGNFKNLREFVFKNIDGYFK IYSKHTPINLVRDLPQGFSALEPLVDLPIGINITRFQTLLALH RSYLTPGDSSSGWTAGAAAYYVGYLQPRTFLLKYNENGTI TDAVDCALDPLSETKCTLKSFTVEKGIYQTSNFRVQPTESI VRFPNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSV LYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVR QIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGN YNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCY FPLQSYGFQPTNGVGYQPYRVVVLSFELLHAPATVCGPKK STNLVKNKCVNFNFNGLTGTGVLTESNKKFLPFQQFGRDI ADTTDAVRDPQTLEILDITPCSFGGVSVITPGTNTSNQVAVL YQDVNCTEVPVAIHADQLTPTWRVYSTGSNVFQTRAGCLI GAEHVNNSYECDIPIGAGICASYQTQTNSPRRARSVASQSI IAYTMSLGAENSVAYSNNSIAIPTNFTISVTTEILPVSMTKTS VDCTMYICGDSTECSNLLLQYGSFCTQLNRALTGIAVEQD KNTQEVFAQVKQIYKTPPIKDFGGFNFSQILPDPSKPSKRS FIEDLLFNKVTLADAGFIKQYGDCLGDIAARDLICAQKFNG LTVLPPLLTDEMIAQYTSALLAGTITSGWTFGAGAALQIPF AMQMAYRFNGIGVTQNVLYENQKLIANQFNSAIGKIQDSLS STASALGKLQDVVNQNAQALNTLVKQLSSNFGAISSVLND ILSRLDKVEAEVQIDRLITGRLQSLQTYVTQQLIRAAEIRAS ANLAATKMSECVLGQSKRVDFCGKGYHLMSFPQSAPHGV VFLHVTYVPAQEKNFTTAPAICHDGKAHFPREGVFVSNGT HWFVTQRNFYEPQIITTDNTFVSGNCDVVIGIVNNTVYDPL QPELDSFKEELDKYFKNHTSPDVDLGDISGINASVVNIQKE IDRLNEVAKNLNESLIDLQELGKYEQYIKWP
TSCCSCLKGCCSCGSCCKFDEDDSEP
VLKGVKLHYT
Table 2
SARS CoV-2 S protein domains
Subunit Positions Domain
S1 1-13 Signal peptide (N-terminus)
14-305 N-terminus domain (NTD)
306-318 Uncharacterized fragment
319-541 Receptor-binding domain (RBD)
542-787 Uncharacterized fragment
S2 788-806 Fusion peptide (FP)
807-911 Uncharacterized fragment
912-984 Heptapeptide repeat sequence 1 (HR1)
985-1162 Uncharacterized fragment
1163-1213 Heptapeptide repeat sequence 2 (HR2)
1238-1273 Cytoplasm tail (CT)
The Receptor-binding domain (RBD) continues to be of great interest to the researchers. RBD boundaries are estimated differently by different authors, namely: R319 — F541 (refs. see [3]) or T333 — T523 [1]. Within this region, the Receptor-binding motif
(RBM438.508) and amino acid residues N439,
L452, T47K, E484, Q4'
See Table 2 for color code. Receptor-binding motif (RBM) S438 — Y508 underlined. Hereinafter, the primary structures of SARS CoV-2 proteins are given according to Uniprot database [5].
S protein molecule consists of subunits and domains (Table 2).
'-452 47K
and N501 are considered critical for binding affinity [6]:
SNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGS TPCNGVEGFNCYFPLQSYGFQPTNGVGYQPY.
At the border between subunits S1 and S2, the S protein molecule forms a loop. The authors believe that the loop is a key component in determining virus stability and transmission [7].
There are more than two dozen hepta- and octamers homologous to human proteins in the S protein molecule. Localization of these n-mers is shown in the Table 3.
Of all the regions listed in Table 3 that are homologous to human proteins, only two, KLNDLCF386-392 and DEVRQIA405-411, are located in RBD and none are located in RBM.
Table 3 shows that heptamer KLNDLCF386-392 is homologous to motif in the interleukin 7 (IL-7149-155) molecule. In severe cases of COVID-19 patients have increased level of IL-7 [8, 9], which is highly associated with disease severity [10]. IL-7 administered to critically ill COVID-19 patients has been associated with a return of lymphocytes to normal levels [11]. As a vaccine adjuvant, IL-7
Table 3
Localization of homologous hepta- / octamers in the S protein and human proteins
Subunit SARS CoV-2 S protein domain In S protein In human proteins
S1 Signal peptide (N-terminus)1-13 none -
N-terminus domain NTD14-305 DKVFRSS40-46 Zinc finger protein 52 8275.281
FLPFFSN55-61 OTU domain-containing protein 6A185-191
vsgtngt70-76 Lysosome-associated membrane glycoprotein 1171-177
sllivnn116-122 ATP-binding cassette sub-family A member 10825-831
FKNLREF186-192 Isovaleryl-CoA dehydrogenase, mitochondrial77-83
TRFQTLL236-242 Disheveled-associated activator of morphogenesis 2251-257
K|YSKHT202-208 Uncharacterized protein C1orf1057-13
SSSGWTA254-26o Uncharacterized protein KIAA1109 (Fragment)610-616
Uncharacterized fragment306-318 none -
Receptor-binding domain RBD319-541 KLNDLCF386-392 Interleukin-7149-155
DEVRQIA405-411 Histone-lysine N-methyltransferase 2C4530-4536
Uncharacterized fragment542-787 VYSTGSN635-641 Neural cell adhesion molecule L1-like protein341-347
IGAGICA666-672 Hepatitis A virus cellular receptor 2205-211
SPRRARS680-686 Hermansky-Pudlak syndrome 1 protein258-264
RRARSVAS682-689 Amiloride-sensitive sodium channel subunit alpha201-208
S2 Fusion peptide FP788-806 none -
Uncharacterized fragment807-911 VTLADAG826-832 Non-receptor tyrosine-protein kinase TNK1440-446
Ending of the table 3
Subunit SARS CoV-2 S protein domain In S protein In human proteins
gltvlpp857.863 FH1/FH2 domain-containing protein 3972-978
lpplltd861.867 Maestro heat-like repeat-containing protein family member 9250-256
Heptapeptide repeat sequence 1 HR1912-984 SSTASAL939-945 40S ribosomal protein S13143-149
LVKQLSS962-968 E3 SUMO-protein ligase PIAS1284-290
Uncharacterized fragment985-1162 KVEAEVQ986-974 Emilin-3625-63i
TGRLQSL998-1004 Neuron navigator 31610-1616
LIRAAEI1012-1018 Unconventional myosin-XVIIIa1352-1358; SP-A receptor subunit SP-R210 alphaS894-900
LDKYFKN1152-1158 Follistatin-related protein 1149-155
Heptapeptide repeat sequence 2 HR21163-1213 NASVVNI1173-1179 Thyroid adenoma-associated protein1022-1028
EIDRLNE1182-1188 Protein SETSIP64-70; Protein SET54-60
Transmembrane tail TM1214-1237 none -
Cytoplasm tail CT1238-1273 DEDDSEPVi257-1264 Unconventional myosin-XVI1404-1421
[3, adapted]. Hereinafter, the primary structures of human proteins are given according to Uniprot database — Homo sapiens [5].
Table 4
Localization of homologous hepta- / octamers in the transmembrane domain8-38 E protein and human proteins [3, adapted]
could enhance the immune responses to vaccines against SARS CoV-2 [12]. IL-7 is beneficial cytokine to the pathophysiology of COVID-19 [13]. At the same time, IL-7 induces SARS CoV-2 receptor ACE2 expression in human vascular endothelial cells [14]. In patients with COVID-19, respiratory failure is associated with
an increase in systemic blood pressure, probably due to modulation of the renin-angiotensin-aldosterone system by SARS-CoV-2 infection [15].
Heptamer DEVRQIA405-411 is homologous to motif in the His-tone-lysine N-methyltransferase 2C (HLNMT 2C4530-4536). Histone methylation plays an important role in such a critical process as the epigenetic regulation of genes [16].
Presumably, IL-7 is an outpost defense trigger. When cell destruction begins in COVID-19, IL-7 turns on the last reserve of life, activating immunological memory cells. SARS CoV-2 tricks the immune system into presenting a motif homologous to IL-7.
S protein is involved in the organization of virion assembly in the intermediate compartment ER-Golgi [17].The C-terminal truncation of the protein S molecule results in a variant that easily passes through the Golgi complex to the plasma membrane in a pre-activated conformation, causing increased syncytium formation [18].
Envelope small membrane protein
Envelope small membrane (E) protein is the shortest (75 ami-no acid residues) of all SARS CoV-2 structural proteins.
MYSFVSEETGTLIVN SVLLFLAFVVFLLVTLAILTALRLCA
YCCNIVNVSLVKPSFYVYSRVKNLNSSRVPDLLV
Transmembrane domain8-38 is underlined. Hereinafter, n-mers homologous to human proteins are highlighted in red.
Only a small part of it, namely heptamer M1 - Y6, protrudes from the virion outwards.
In E protein In human proteins
vnsvllf14.2O Heterogeneous nuclear ribonucleoprotein L191-197
vnsvllfl14-21 Ran-binding protein 6409-416
nsvllfl15-21 Lysosomal amino acid transporter 1 homolog133-139
SVLLFLA16-22 Cytochrome P450 2B64-10 ; Cytochrome P450 2B74-10; GPI ethanolamine phosphate transferase 35-11
lafvvfl21-27 Solute carrier family 15 member 4235-241
VFLLVTL25.3I Alpha-(1,3)-fucosyltransferase 1020-26
LAILTAL31.37 Transient receptor potential cation channel subfamily M member 6394-400 ; Transient receptor potential cation channel subfamily M member 3465-471
TALRLCA35.4ib Protein disulfide-isomerase TMX38-14
Heptamer TALRLCA35.41 is located at the junction of the transmembrane domain, and internal domain 39-75.
E protein contains eight hepta- / octamer homologous to human proteins (Table 4).
Homologous n-mers merge into a single 2octamer, which is almost entirely located in the thickness of the envelope of the virion. A random selection of 28 letters in a word would require an astronomical number of iterations: 2028 = 2.7 • 1036. (This number is slightly less than the mass of the Earth, measured in nanograms.)
The degree of homology within this 28-measure can be represented as follows:
VNSVLLFLAfvVFLlvtLAILTALrlca,
where the size of the letters corresponds to the frequency of the viral hepta- / octamers in the human proteome.
Besides, the protein E transmembrane domain contains an octamer and a heptamer, homologous to the proteins of some gut bacteria Lactobacillus sp. and even cereals, including corn Zea mays, sorghum Sorghum bicolor, wheat Triticum aestivum, and barley Hordeum vulgare (Table 5).
Table 5
Localization of some of homologous n-mers in the E protein and human gut proteome [3]
In E protein In bacterial and plant proteins
afvvfllv22-29 Lpp126 large-conductance mechanosensitive channel: Lactobacillus caseiM-87; L. paracasei8M7; L. florum80-87
TLAILTA30-36 Uncharacterized proteins: Zea mays9()-164; Sorghum bicolor97-127; Triticum aestivum116-190; Hordeum vulgare87-161
E protein is integrated into the human cell membrane; later it is transported closer to the endoplasmic reticulum and the Golgi apparatus, where viral replication occurs [19]. E protein can affect the properties of S proteins and contribute to the assembly of viral particles [20].
Membrane protein
Membrane (M) protein consists of 222 amino acid residues, and its structure contains six heptamers homologous to human proteins (Table 6).
MADSNGTITVEELKKLLEQWNLVIGFLFLTWICLLQFAYAN RNRFLYIIKLIFLWLLWPVTLACFVLAAVYRINWITGGIAIAMACLV GLMWLSYFIASFRLFARTRSMWSFNPETNILLNVPLHGTILTRP LLESELVIGAVILRGHLRIAGHHLGRCDIKDLPKEITVATSRTLSY YKLGASQRVAGDSGFAAYSRYRIGNYKLNTDHSSSSDNIALLVQ
Four heptamers are located close to the N-terminus of the molecule, merging into a single decamer V10 - Q19. Taking into account the number of homologous amino acid residues, this decamer can be represented as follows:
vEELKKLLEq.
Table 6
Localization of homologous heptamers in the M protein and human proteins [3]
7bIn M protein In human proteins
VEELKKL10-16 Glutaredoxin-related protein 5, mitochondrial135-141
eelkkll11-17 GDP-fucose protein O-fucosyltransferase 2340-346
elkklle12-18 Cullin-1335-341
LKKLLEQ13-19 Filamin-A-interacting protein 1211-217
LLESELV133-139 Leucine-rich repeat-containing protein 7 1 439-445
AGDSGFA188-194 Myosin-14359-3g5
Outside of the decamer, there are two homologous heptamers. Protein M is a candidate for participation in mimicry processes.
Like E protein, M protein can affect the properties of S proteins and contribute to the assembly of viral particles [20].
S, E, and M proteins cause Golgi fragmentation; disruption of the Golgi apparatus appears to be a critical component of SARS CoV-2 replication [21].
Nucleoprotein
The nucleoprotein (N-protein) consists of 419 amino acid residues and contains eleven heptamers homologous to human proteins (Table 7).
MSDNGPQNQRNAPRITFGGPSDSTGSNQNGERSGARSKQR RPQGLPNNTASWFTALTQHGKEDLKFPRGQGVPINTNSSPDDQ IGYYRRATRRIRGGDGKMKDLSPRWYFYYLGTGPEAGLPYGA NKDGIIWVATEGALNTPKDHIGTRNPANNAAIVLQLPQGTTLPK GFYAEGSRGGSQASSRSSSRSRNSSRNSTPGSSRGTSPARM AGNGGDAALALLLLDRLNQLESKMSGKGQQQQGQTVTKKSAA EASKKPRQKRTATKAYNVTQAFGRRGPEQTQGNFGDQELIRQ GTDYKHWPQIAQFAPSASAFFGMSRIGMEVTPSGTWLTYTGAI KLDDKDPNFKDQVILLNKHIDAYKTFPPTEPKKDKKKKADETQA LPQRQKKQQTVTLLPAADLDDFSKQLQQSMSSADSTQA
Some of the heptamers fuse into several rather long fragments, including the decamer A173 - A182, and 13-mer S404 - S416. It increases the likelihood of the protein involvement in provoking an autoimmune response. Protein N is located completely inside the SARS CoV-2 virion and cannot participate in mimicry, but can be involved in provoking an autoimmune response.
In comparison with SARS-CoV, SARS-CoV-2 contains six times more acetyl-lysine residues. This suggests that acetylation of N proteins plays crucial roles in SARS-CoV-2 functions [22].
NONSTRUCTURAL PROTEINS
All nonstructural proteins of SARS CoV-2 (ORF3a, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF1Q, ORF14, RPP 1a, and
Table 7
Localization of homologous heptamers in the N protein and human proteins [3]
In N protein In human proteins
rpqglpn4147 GATOR complex protein WDR59757-763
rgqgvpi68_74 Putative uncharacterized protein encoded by LINC00346154-160
nsspddq77.83 NEDD4-binding protein 2154-160
gkmkdls99,05 Chromodomain-helicase-DNA-binding protein 1-like770-776
vlqlpqgI57.I63 Prestin92-98
AEGSRGG173-179 snRNA-activating protein complex subunit32-8
srggsqaI76_I82 Ras-associating and dilute domain-containing protein886-892
kadetqa375-38I Myopalladin90-96
LLpAADL394-400 Probable E3 ubiquitin-protein ligase HERC11098-1104
SKQLQQS404-410 Codanin-1259-265
smssads410-416 Protein PRRC2B416-422
RPP 1ab) are located completely inside the SARS CoV-2 virion and, by definition, cannot be involved in the process of mimicry. What remains to consider the possibility of their implication in provoking an autoimmune process [3].
ORF3a protein
ORF3a protein molecule consists of 275 amino acid residues:
MDLFMRIFTIGTVTLKQGEIKDATPSDFVRATATIPIQASLPFG WLIVGVALLAVFQSASKIITLKKRWQLALSKGVHFVCNLLLLF VTVYSHLLLVAAGLEAPFLYLYALVYFLQSINFVRIIMRLWLCW KCRSKNPLLYDANYFLCWHTNCYDYCIPYNSVTSSIVITSGDG TTSPISEHDYQIGGYTEKWESGVKDCVVLHSYFTSDYYQLYS TQLSTDTGVEHVTFFIYNKIVDEPEEHVQIHTIDGSSGVVNPVME PIYDEPTTTTSVPL
In the ORF3a protein molecule, there are five heptamers homologous to human proteins (Table 8).
The heptamers scattered along the entire length of its mol ecule do not form long n-mers anywhere else. ORF3a does not appear to be involved in provoking an autoimmune response.
ORF6 protein
ORF6 protein molecule consists of 61 amino acid residues:
MFHLVDFQVTIAEILLIIMRTFKVSIWNLDYIINLIIKNLSKSLTENKY SQLDEEQPMEID
In the molecule, there is no heptamers homologous to human proteins.
ORF7a protein
ORF7a protein molecule consists of 121 amino acid residues:
MKIILFLALITLATCELYHYQECVRGTTVLLKEPCSSGTYEGNSPF HPLADNKFALTCFSTQFAFACPDGVKHVYQLRARSVSPKLFIRQ EEVQELYSPIFLIVAAIVFITLCFTLKRKTE
In the ORF7a protein molecule, there are only two heptamers homologous to human proteins located in close proximity to each other (Table 9).
Table 9
Localization of homologous heptamers in the ORF7a protein and human proteins [3]
Table 8
Localization of homologous heptamers in the ORF3a protein and human proteins [3]
In ORF3a protein In human proteins
VGVALLA48-54 Manganese-transporting ATPase 13A1876-882
LLVAAGL95-101 Glycerophosphoinositol inositolphosphodiesterase GDPD2129-135
KCRSKNPi32-i38 Vacuolar protein sorting-associated protein 13A2066-2972
SVTSSIVi62-i68 Protein piccolo2779-2785
tqlstdt217-223 Septin-14418-424
In ORF7a protein In human proteins
VAAIVFI104-110 Transmembrane protein 255B86-92
FTLKRKTii4-i20 Cytosolic 5'-nucleotidase 3A36-42
It is possible that ORF7a is involved in provoking an autoimmune response.
ORF7b protein
ORF7b protein molecule consists of 43 amino acid residues:
MIELSLIDFYLCFLAFLLFLVLIMLIIFWFSLELQDHNETCHA
In this polypeptide, there are only one heptamer homologous to the human protein (Table 10).
Table 10
Localization of the homologous heptamer in ORF7b and a human protein [3]
In ORF7b protein In human protein
IIFWFSL26-32 Olfactory receptor 7D4151-157
Table 12
Localization some of homologous hepta- / octamers in ORF9b protein and human proteins [3]
In ORF9b protein In human proteins
LVDPQIQL14-21 Valine-tRNA ligase, mitochondrial996-1002
MENAVGR26-32 Neprilysin419-425
LGSPLSL^ Stress-responsive DNAJB4-interacting membrane protein 137-43
GSPLSLN49-55 E3 ubiquitin-protein ligase HERC24533-4539
TEELPDEвл-go KH homology domain-containing protein 4465-471
ELPDEFVVв6-gз Maestro heat-like repeat-containing protein family member 2B103-110
The ORF7b protein may be involved in provoking an autoimmune response and, in particular, contribute to olfactory dysfunction.
ORF8 protein
ORF8 protein molecule consists of 121 amino acid residues:
MKFLVFLGIITTVAAFHQECSLQSCTQHQPYVVDDPCPIHFYSK WYIRVGARKSAPLIELCVDEAGSKSPIQYIDIGNYTVSCLPFTINC QEPKLGSLVVRCSFYEDFLEYHDVRVVLDFI
In this polypeptide, there are three heptamers homologous to human proteins (Table 11).
Table 11
Localization of homologous heptamers in the ORF8 protein and human proteins [3]
In ORF8 protein In human proteins
LVFLGII4-10 Zinc finger protein 48649-55
LGIITTV7-13 D-2-hydroxyglutarate dehydrogenase, mitochondrial262-268
KLGSLVVg4-1oo Sodium leak channel non-selective protein505-511
In this case, two heptamers merge into a decamer L4 - V13. Due to the fusion of two heptamers into a decamer L4 - V13, the ORF8 can be involved in provoking an autoimmune response.
ORF9b protein
ORF9b protein molecule consists of 97 amino acid residues:
MDPKISEMHPALRLVDPQIQLAVTR MENAVGRDQNNVGP KVYPIILRLGSPLSLNMARKTLNSLEDKAFQLTPIAVQMTKLAT TEELPDEFVVVTVK
In the ORF9b protein molecule, there are six hepta- / octamers, homologous to human proteins (Table 12).
Some of these hepta- / octamers merge into octamer L48 - N55 and decamer T84 - V93.
Octamer ELPDeFvv86-93 is homologous to the Maestro heatlike repeat-containing protein family member 2B, which may play a role in the sperm capacitation [23]. Male reproductive dysfunction has been proposed as a likely consequence of COVID-19 [24].
After the destruction of the SARS CoV-2 virion, ORF9b can take part in provoking an autoimmune response. This protein plays a special role in hijacking mitochondrial metabolic processes in COVID-19 infection [25].
ORF10 protein
ORFIO protein (traditional name, but more correctly: polypeptide) molecule consists of 38 amino acid residues:
MGYINVFAIPFTIYSLLLCRMNSRSYTAQVGIVNFNLT In the molecule, there is no heptamers homologous to human proteins.
ORF14 protein
ORF14 protein (synonym: ORF9c) molecule consists of 73 amino acid residues:
mlqscynflkeqhcqkastqkgaeaavkpllvphhvvatvqei qlqaavgellllewlamavmllllcccltd
In the molecule, there is no heptamers homologous to human proteins.
Replicase polyprotein RPP 1a
Replicase polyprotein 1a (RPP 1a) consists of 4405 amino acid residues.
MESLVPGFNEKTHVQLSLPVLQVRDVLVRGFGDSVEEVLSEARQHLKDGTCGL VEVEKGVLPQLEQPYVFIKRSDARTAPHGHVMVELVAELEGIQYGRSGETLGVL VPHVGEIPVAYRKVLLRKNGNKGAGGHSYGADLKSFDLGDELGTDPYEDFQEN WNTKHSSGVTRELMRELNGGAYTRYVDNNFCGPDGYPLECIKDLLARAGKASCT LSEQLDFIDTKRGVYCCREHEHEIAWYTERSEKSYELQTPFEIKLAKKFDTFN GECPNFVFPLNSIIKTIQPRVEKKKLDGFMGRIRSVYPVASPNECNQMCLSTLM KCDHCGETSWQTGDFVKATCEFCGTENLTKEGATTCGYLPQNAVVKIYCPACH NSEVGPEHSLAEYHNESGLKTILRKGGRTIAFGGCVFSYVGCHNKCAYWVPRA SANIGCNHTGVVGEGSEGLNDNLLEILQKEKVNINIVGDFKLNEEIAIILASFSAS TSAFVETVKGLDYKAFKQIVESCGNFKVTKGKAKKGAWNIGEQKSILSPLYAFA SEAARVVRSIFSRTLETAQNSVRVLQKAAITILDGISQYSLRLIDAMMFTSDLATN NLVVMAYITGGVVQLTSQWLTNIFGTVYEKLKPVLDWLEEKFKEGVEFLRDGW EIVKFISTCACEIVGGQIVTCAKEIKESVQTFFKLVNKFLALCADSIIIGGAKLKAL NLGETFVTHSKGLYRKCVKSREETGLLMPLKAPKEIIFLEGETLPTEVLTEEVVLKT GDLQPLEQPTSEAVEAPLVGTPVCINGLMLLEIKDTEKYCALAPNMMVTNNTFT LKGGAPTKVTFGDDTVIEVQGYKSVNITFELDERIDKVLNEKCSAYTVELGTEVN EFACVVADAVIKTLQPVSELLTPLGIDLDEWSMATYYLFDESGEFKLASHMYCS FYPPDEDEEEGDCEEEEFEPSTQYEYGTEDDYQGKPLEFGATSAALQPEEEQE EDWLDDDSQQTVGQQDGSEDNQTTTIQTIVEVQPQLEMELTPVVQTIEVNSFSG YLKLTDNVYIKNADIVEEAKKVKPTVVVNAANVYLKHGGGVAGALNKATNNAM QVESDDYIATNGPLKVGGSCVLSGHNLAKHCLHVVGPNVNKGEDIQLLKSAYE NFNQHEVLLAPLLSAGIFGADPIHSLRVCVDTVRTNVYLAVFDKNLYDKLVSSFL EMKSEKQVEQKIAEIPKEEVKPFITESKPSVEQRKQDDKKIKACVEEVTTTLEE TKFLTENLLLYIDINGNLHPDSATLVSDIDITFLKKDAPYIVGDVVQEGVLTAVVIP TKKAGGTTEMLAKALRKVPTDNYITTYPGQGLNGYTVEEAKTVLKKCKSAFYI LPSIISNEKQEILGTVSWNLREMLAHAEETRKLMPVCVETKAIVSTIQRKYKGIK IQEGVVDYGARFYFYTSKTTVASLINTLNDLNETLVTMPLGYVTHGLNLEEAAR YMRSLKVPATVSVSSPDAVTAYNGYLTSSSKTPEEHFIETISLAGSYKDWSYSG QSTQLGIEFLKRGDKSVYYTSNPTTFHLDGEVITFDNLKTLLSLREVRTIKVFTT VDNINLHTQVVDMSMTYGQQFGPTYLDGADVTKIKPHNSHEGKTFYVLPNDD TLRVEAFEYYHTTDPSFLGRYMSALNHTKKWKYPQVNGLTSIKWADNNCYL ATALLTLQQIELKFNPPALQDAYYRARAGEAANFCALILAYCNKTVGELGDVRE TMSYLFQHANLDSCKRVLNVVCKTCGQQQTTLKGVEAVMYMGTLSYEQFKKG VQIPCTCGKQATKYLVQQESPFVMMSAPPAQYELKHGTFTCASEYTGNYQCG HYKHITSKETLYCIDGALLTKSSEYKGPITDVFYKENSYTTTIKPVTYKLDGVVCT EIDPKLDNYYKKDNSYFTEQPIDLVPNQPYPNASFDNFKFVCDNIKFADDLNQL TGYKKPASRELKVTFFPDLNGDVVAIDYKHYTPSFKKGAKLLHKPIVWHVNNAT NKATYKPNTWCIRCLWSTKPVETSNSFDVLKSEDAQGMDNLACEDLKPVSEE VVENPTIQKDVLECNVKTTEVVGDIILKPANNSLKITEEVGHTDLMAAYVDNSSLT IKKPNELSRVLGLKTLATHGLAAVNSVPWDTIANYAKPFLNKVVSTTTNIVTRCL NRVCTNYMPYFFTLLLQLCTFTRSTNSRIKASMPTTIAKNTVKSVGKFCLEASFN YLKSPNFSKLINIIIWFLLLSVCLGSLIYSTAALGVLMSNLGMPSYCTGYREGYLN STNVTIATYCTGSIPCSVCLSGLDSLDTYPSLETIQITISSFKWDLTAFGLVAEWFL AYILFTRFFYVLGLAAIMQLFFSYFAVHFISNSWLMWLIINLVQMAPISAMVRMYIF FASFYYVWKSYVHVVDGCNSSTCMMCYKRNRATRVECTTIVNGVRRSFYVYA NGGKGFCKLHNWNCVNCDTFCAGSTFISDEVARDLSLQFKRPINPTDQSSYIV DSVTVKNGSIHLYFDKAGQKTYERHSLSHFVNLDNLRANNTKGSLPINVIVFDG KSKCEESSAKSASVYYSQLMCQPILLLDQALVSDVGDSAEVAVKMFDAYVNTF SSTFNVPMEKLKTLVATAEAELAKNVSLDNVLSTFISAARQGFVDSDVETKDV VECLKLSHQSDIEVTGDSCNNYMLTYNKVENMTPRDLGACIDCSARHINAQVA KSHNIALIWNVKDFMSLSEQLRKQIRSAAKKNNLPFKLTCATTRQVVNVVTTK IALKGGKIVNNWLKQLIKVTLVFLFVAAIFYLITPVHVMSKHTDFSSEIIGYKA IDGGVTRDIASTDTCFANKHADFDTWFSQRGGSYTNDKACPLIAAVITREV GFVVPGLPGTILRTTNGDFLHFLPRVFSAVGNICYTPSKLIEYTDFATSACVL
AAECTIFKDASGKPVPYCYDTNVLEGSVAYESLRPDTRYVLMDGSIIQFPNT YLEGSVRVVTTFDSEYCRHGTCERSEAGVCVSTSGRWVLNNDYYRSLPGV FCGVDAVNLLTNMFTPLIQPIGALDISASIVAGGIVAIVVTCLAYYFMRFRRAF GEYSHVVAFNTLLFLMSFTVLCLTPVYSFLPGVYSVIYLYLTFYLTNDVSFLA HIQWMVMFTPLVPFWITIAYIICISTKHFYWFFSNYLKRRVVFNGVSFSTF EEAALCTFLLNKEMYLKLRSDVLLPLTQYNRYLALYNKYKYFSGAMDTT SYREAACCHLAKALNDFSNSGSDVLYQPPQTSITSAVLQSGFRKMAFP SGKVEGCMVQVTCGTTTLNGLWLDDVVYCPRHVICTSEDMLNPNYEDLLI RKSNHNFLVQAGNVQLRVIGHSMQNCVLKLKVDTANPKTPKYKFVRIQPG QTFSVLACYNGSPSGVYQCAMRPNFTIKGSFLNGSCGSVGFNIDYDCVSF CYMHHMELPTGVHAGTDLEGNFYGPFVDRQTAQAAGTDTTITVNVLAWLYAA VINGDRWFLNRFTTTLNDFNLVAMKYNYEPLTQDHVDILGPLSAQTGIAVLDM CASLKELLQNGMNGRTILGSALLEDEFTPFDVVRQCSGVTFQSAVKRTIKGT HHWLLLTILTSLLVLVQSTQWSLFFFLYENAFLPFAMGIIAMSAFAMMFVKHKH AFLCLFLLPSLATVAYFNMVYMPASWVMRIMTWLDMVDTSLSGFKLKDCVMY ASAVVLLILMTARTVYDDGARRVWTLMNVLTLVYKVYYGNALDQAISMWALIISV TSNYSGVVTTVMFLARGIVFMCVEYCPIFFITGNTLQCIMLVYCFLGYFCTCYFGL FCLLNRYFRLTLGVYDYLVSTQEFRYMNSQGLLPPKNSIDAFKLNIKLLGVGGK PCIKVATVQSKMSDVKCTSVVLLSVLQQLRVESSSKLWAQCVQLHNDILLAKDT TEAFEKMVSLLSVLLSMQGAVDINKLCEEMLDNRATLQAIASEFSSLPSYAAFAT AQEAYEQAVANGDSEVVLKKLKKSLNVAKSEFDRDAAMQRKLEKMADQAMTQ MYKQARSEDKRAKVTSAMQTMLFTMLRKLDNDALNNIINNARDGCVPLNIIPLT TAAKLMVVIPDYNTYKNTCDGTTFTYASALWEIQQVVDADSKIVQLSEISMDNSP NLAWPLIVTALRANSAVKLQNNELSPVALRQMSCAAGTTQTACTDDNALAYYN TTKGGRFVLALLSDLQDLKWARFPKSDGTGTIYTELEPPCRFVTDTPKGPKVK YLYFIKGLNNLNRGMVLGSLAATVRLQAGNATEVPANSTVLSFCAFAVDAAKAY KDYLASGGQPITNCVKMLCTHTGTGQAITVTPEANMDQESFGGASCCLYCRCH IDHPNPKGFCDLKGKYVQIPTTCANDPVGFTLKNTVCTVCGMWKGYGCSCDQL REPMLQSADAQSFLNGFAV
In the RPP 1a molecule, there are eleven octamers (Table 13) and more than a hundred heptamers homologous to human proteins.
Some of the octamers are found in more than one human protein, some fold into long n-mers, for example 16-mer EDIQLLKSAYENFNQH1126-1141, 14-mer EVEKGVLPQLEQPY55-68 and 13-mer SVEEVLSEARQHL34-46. The question of the participation of this large molecule in provoking an autoimmune response requires further study.
Replicase polyprotein RPP 1ab
Replicase polyprotein 1ab (RPP 1ab) consists of 7096 amino acid residues. In the RPP 1ab molecule, there are 210 hepta- / octamer homologous to human proteins. Some of them fold into long (more than 15 amino acid residues) n-mers. The role of this huge molecule in provoking an autoimmune response also requires study.
EVASION AND PROVOCATION OF AUTOIMMUNE RESPONSE
Based on the fact that the external SARS CoV-2 proteins are the first to contact host's immune system, while the internal proteins are only the second, it would be reasonable to divide the proteins of the virus into external and internal proteins. The difference from the generally accepted classification (structural / nonstructural) is
Table 13
Localization of homologous octamers in RPP 1a and human proteins [3, adapted]
minimal. The first group includes proteins S, E and M, the second — all the others, including the N protein. We will consider proteins of the first group as participants in the processes of mimicry and the second as provocateurs of an autoimmune response.
External proteins and mimicry
In the IT terminology, the word evasion means bypassing an information security device to deliver malware without being detected by the recipient. Virologists have long been familiar with viral immune evasion, having a variety of expressions to describe it, such as: to avoid the immune response, to outwit the immune system, to outmaneuver your hosts, to subvert the host cellular response, viral mimicry, camouflage, subversion and piracy. The growing virulence of SARS CoV-2 indicates that the virus's ability to deceive the innate immune system improves with some new mutations.
To mislead the immune system, the virus could have hijacked some regions of the genetic code from previous hosts. That makes its proteins similar to human proteins. Knowledge of the homology between the virus and human proteins might help understand the mechanisms of mimicry in the moment of infection and during the subsequent autoimmune response.
For evasion to occur, the virus must appear in front of the immune system and tell it: don't shoot! I am one of you! The traditional naming of a password is not suitable for such a message,
since a password, by definition, must be known by a very limited number of people or devices. Virology needs a term for a universal password, known to an unlimited number of participants on both sides of the information exchange. There is a suitable term in IT — shibboleth. Reported to a computer security system without distortion, the shibboleth allows an intruder (person or device) to gain access to the desired resources.
The word shibboleth, borrowed from the Bible (Judges 12: 5-6), is used by linguists and literary men (see Shitbroleeth in episode 16 of Ulysses by James Joyce), from whom psychologists and psychiatrists adopted it. Dr Dmitry Kormilets in a private communication suggested using this term in virology as well. In our interpretation, shibboleth is an area of the surface of virion, according to which the immune system must mistakenly recognize the virus as a part of the host organism and turn off the mechanisms designed to inactivate and / or destroy the intruder.
Some viral proteins are homologues of human proteins. It appears they have been hijacked from the host and included in their own genomes [26].
Tables 3-6 show a lot of motifs common to the external SARS CoV-2 proteins and humans. Which of them are directly involved in mimicry, it is now impossible to say. One can only point to the motifs in the most functionally important regions of the external proteins of SARS CoV-2 and human proteins. In addition, those regions of the external proteins of SARS CoV-2, in which the frequency of occurrence of homologous regions is the highest, deserve special attention.
Perhaps this is how the SARS CoV-2 protects its most important site (RBD) from the immune system.
The narrow region of the E protein transmembrane domain contains a variety of motifs homologous to proteins from humans, food, and intestinal bacteria (Tables 4 and 5). In this regard, the participation of E protein in mimicry seems to be the most probable.
In the structure of M protein, there is also a high "concentration" of motifs homologous to human ones (Table 6). In the protein M, four heptamers homologues of human proteins are fused into a decamer V10-Q19. The hydrophilic composition indicates a possible contact with the extracellular environment and the host's immune system. This outer protein is the second most likely candidate for the role of mimicry organizer.
Provoking of Autoimmune Response
The most likely candidate is ORF9b protein. In its small molecule, regions which are homologous to human proteins account for 34.0% (33 out of 97), the highest value of this indicator among all internal proteins. The biggest structural difference is found between SARS CoV-2 RF9b protein and similar bat and pangolin proteins compared to other SARS CoV-2 proteins, which indicates active mutagenesis [27].
The polyprotein molecules RPP 1a and RPP 1a b are huge, as is the number of homologous motifs in them. The possibility that the motifs take part in provoking an autoimmune response has not yet been proven. Enzymes and especially enzymes of
In Replicase polyprotein 1a In human proteins
SVEEVLS34-40 FLJ00176 protein (Fragment)260-266
SEARQHL40-46 Cytokine-inducible inhibitor of signaling type ^¡¡-^
EVEKGVLP55-62 Bifunctional heparan sulfate N-deacetylase/N-sulfotransferase 1214-221
ESGLKTIL390-397 Annexin A7404-411
reetgllm724-731 Estrogen-related receptor gamma30-37
GGSCVLSG1100-1107 Sorting nexin-27112-119
diqllksa1127-1134 Echinoderm microtubule-associated protein-like 138-45
RRSFYVYA2431-2438 Transmembrane protein adipocyte-associated 1225-232
AKKNNLPF2733-2740 Acyl-CoA:lysophosphatidylglycerol acyltransferase 1199-206
YNYEPLTQ3500-3507 DNA helicase199-206
SLKELLQN3530-3537 Centromere protein I496-503
DTSLSGFK3671-3678 Solute carrier family 12 member 7995-1002
PEANMDQE4312-4319 Arachidonate 5-lipoxygenase-activating protein^
the cell cycle are evolutionarily highly conserved. In the process of disintegration of microorganisms, permanent inhabitants of the human intestine, peptides homologous to human proteins must be released into the intestinal lumen. Perhaps it is they who interact with the host's immune system and tune it to non-resistance to virion proteins.
Dysfunction of olfactory and taste receptors
ACE2 protein has been found at high levels in the human olfactory epithelium. May this explain COVID-19-associated olfactory dysfunction [28]?
In the RPP 1a molecule, heptamers SCGNFKV505-511 and AIFYLIT2785-2791 are homologous to human Olfactory receptor proteins 52N2190-196 and 2W132-38, respectively. ORF7b contains a hep-tamer homologous to the Olfactory receptor protein 7D4 and may be involved in provoking an autoimmune response, contributing to olfactory dysfunction. In the RPP 1a, a heptamer LKTLLSL1556-1562 is homologous to the human Bitter taste receptor T2R55181-187.
In S protein, the octamer RRARSVAS682-689 is homologous to the Amiloride-sensitive sodium channel subunit alpha201-208, which is involved in salt taste perception [29].
If homologous motifs in the SARS CoV-2 molecule can trigger an autoimmune response, then these facts may explain why COVID-19 disease so often affects the sense of smell and taste.
Mutations
Mutations are a mechanism for escaping immune responses [4]. Among the SARS CoV-2 proteins, protein S has been studied for mutations. Of the external proteins, it is the most susceptible to mutation [27].
The differences of human S-proteins from Asia, Africa, Europe, North America, South America and Oceania from the reference sequence of the SARS CoV-2 Wuhan-Hu-1 protein, China, are described. There were found 9654 mutations, which correspond to 400 different sites of mutations. RBD alone contained 44 mutations [30]. Of course, far from all of the effects of these mutations have now been studied. Fortunately, not all of them matter. In theory, the mutation can increase, decrease, or not affect the immune response to the S-protein [4].
The D614G mutation changes the conformation of the S protein [4]. SARS CoV and SARS CoV-2 recognize the ACE2 receptor through their S proteins. In the N-terminal domain, the sequences MESEFR153-158 and SYLTPG247-252 are specific for human SARS CoV-2. In RBD, the structural determinants for recognizing human ACE2 are the VGGNY445-449 and EIYQAGSTPCNGV471-483 sequences, as well as the disulfide bridge connecting C480 and C488 [31]. Note that none of the motives mentioned above coincide with regions homologous to human proteins.
S protein of SARS-CoV-2 variant Delta contains eight mutations, namely T„R, G^D, A^-^, R^G, L452R, T478K, P681R, and D950N [32]. S protein of variant Omicron, the most aggressive, contains many mutations, namely V70A, T95I, G142D, V143A, Y144A,
Y145A, G339D S371L S373P S375F K417N N440K G446S S477N T478K
E484A, Q493R, G496S, Q498R, N501Y, Y505H, N655Y, N679K, and P681H,
several of which overlap with those in the Alpha, Beta, Gamma, or Delta variants [33,34]. Due to the huge and continuous stream of data, the topic of mutations in SARS CoV-2 proteins can only be considered in periodicals for now.
CONCLUSION
Judging by the degree of homology between SARS CoV-2 proteins and humans, the main means of bypassing innate immunity (shibboleth) should be the E protein, while the main provocateur of the autoimmune response is the ORF9b protein. Accordingly, the attention of researchers and especially — developers of vaccines against SARS CoV-2 should be paid primarily to these two proteins. It also should be taken into consideration that vaccines affecting such homologous regions can damage proteins of the human body.
Supplementary Materials: None.
Authors Contributions: Equal.
Funding: None.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: None.
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