Alignment of human KAT2A (GCN5) Histone Acetyltransferase and SARS-CoV-2 Orf8 viral proteins

Alignment of human KAT2A (GCN5) Histone Acetyltransferase and SARS-CoV-2 Orf8 viral proteins | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Alignment of human KAT2A (GCN5) Histone Acetyltransferase and SARS-CoV-2 Orf8 viral proteins Steven Lehrer, Peter Rheinstein This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-2235254/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Introduction: The SARS-CoV-2 virus has evolved to mimic an enzyme, KAT2A (lysine acetyltransferase 2A, GCN5), one of the histone proteins that package DNA in the cell nucleus. Gene transcription is deranged because of this mimicry, which reduces antiviral response. An amino acid sequence known as the ARKS motif in histone H3 is modified by KAT2A, which adds acetyl groups and encourages gene transcription. The Orf8 protein from the SARS-CoV-2 virus also has an ARKS motif. KAT2A interacts with Orf8 via ARKS, which modifies it and may cause KAT2A destruction. Using structures from RCSB Protein Data Bank, we examined another way that Orf8 may interfere with KAT2A. Methods: We analyzed two RCSB Protein Data Bank molecules: 1) 1Z4R. Human GCN5 (KAT2A) Histone Acetyltransferase. 2) 7F5F. SARS-CoV-2 Orf8 S84 viral protein. The protein structures were superimposed and aligned on PYMOL v 2.5.0 with the Super command, which super aligns two protein selections. Results: Pymol performed 5 cycles of calculations on 65 aligned atoms of Human KAT2A (GCN5 Histone Acetyltransferase) and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 Angstrom for 51 atoms. Lower values of RMSD indicate that alignment is validated with higher accuracy. RMSD values of 1 Angstrom or less indicate very good alignment. Conclusion: the 51 amino acid alignment of Human KAT2A Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein we identified suggests a significant effect of Orf8 on KAT2A. Orf8 may interfere with KAT2A gene transcription and disrupt host cell ability to regulate gene expression and respond to SARS-CoV-2 infection effectively. Since transcription and translation are upregulated in cancer cells, Orf8 could also be a cancer treatment. Infectious Diseases virus protein alignment Figures Figure 1 Figure 2 Figure 3 Introduction The coronavirus SARS-CoV-2 has already claimed the lives of more than 6 million people, according to the World Health Organization, and the actual death toll may exceed 18 million. More and more people are avoiding severe cases of COVID-19 thanks to vaccines, medications, and immunity from prior infections. Yet the virus's capacity to block the body's immune response, made possible by its arsenal of proteins, is one factor in its propensity to spread [1]. The SARS-CoV-2 virus, according to Kee et al., has evolved to mimic KAT2A (lysine acetyltransferase 2A, GCN5), one of the histone proteins that package DNA in the cell nucleus [2]. Gene transcription is deranged because of this mimicry, which reduces antiviral response. To create chromatin, DNA is wrapped around proteins like histone H3. Among other adjustments, the addition or removal of acetyl groups can modify how tightly chromatin is packed and influence how genes are expressed. An amino acid sequence known as the ARKS motif in H3 is modified by the enzyme KAT2A that adds acetyl groups and encourages gene transcription. Kee et al. found that the Orf8 protein from the SARS-CoV-2 virus also has an ARKS motif. KAT2A interacts with Orf8 via ARKS, which modifies it and may cause KAT2A destruction [3]. Using structures from RCSB Protein Data Bank, we now report another way that Orf8 may interfere with KAT2A. 51 amino acids of Orf8 align closely with KAT2A and could adversely alter its activity. Methods We examined two RCSB Protein Data Bank molecules: 1Z4R. Human GCN5 (KAT2A) Histone Acetyltransferase [4]. 7F5F. SARS-CoV-2 Orf8 S84 viral protein [5]. The protein structures were superimposed and aligned on PYMOL v 2.5.0 with the Super command, which super aligns two protein selections. Super does a sequence-independent structure-based dynamic programming alignment (unlike the align command) followed by a series of refinement cycles intended to improve the fit by eliminating pairing with high relative variability. The Super command is more reliable than align for proteins with low sequence similarity. Results Pymol performed 5 cycles of calculations on 65 aligned atoms of Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 Å for 51 atoms (Table 1). Lower values of RMSD indicate that alignment is validated with higher accuracy. RMSD values of 1 Å or less indicate very good alignment. The two aligned molecules, Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein, are shown in figure 1. The 51-atom alignment is very good. Closeup of aligned beta sheets of Orf8 and KAT2A (fig 1B) indicates TYR 613 of KAT2A is directly underneath VAL 117 of Orf8. According to the UCSC Genome Browser, TYR 613 is in chromosome 17 position 17q12.21.3 42115759, exon 12. This segment is highly conserved in 100 vertebrates, including the rhesus, mouse, dog, elephant, chicken, western clawed frog, and zebrafish. In addition, the segment is within an H3K27Ac mark often found near regulatory elements (fig 2). Figure 3 shows KAT2A with arrow pointing to location of alignment with Orf8. Note the open indentation in this position. Discussion SARS-CoV-2 is quite good at blocking host interferon response. Interferons activate hundreds of genes that prevent viral propagation. SARS-CoV-2 proteins interfere with interferon response steps, sometimes with multiple proteins inhibiting the same step. A protein of 121 amino acid residues and an N-terminal signal sequence are encoded by Orf8 during SARS-CoV-2 infection. Orf8 protein is a dimer that is joined covalently by disulfide links. Orf8 is not necessary for viral replication but does influence how the virus interacts with the host immune system, allowing immune evasion. Orf8 is intensely immunogenic. Persons recovering from SARS-CoV-2 infections have high levels of Orf8 antibodies [6]. The protein structure alignment methods we describe are a powerful way to compare related protein sequences. They can be used to record a variety of information about the matched sequences, such as shared structural function or common evolutionary ancestry. Over the past few decades, protein sequence alignment analyses have become an essential stage in bioinformatics analytic research. Numerous protein databases with information on protein families were created using sequence alignments [7]. H3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is an indication that the lysine residue at the histone H3 protein's N-terminal position 27 has been acetylated. H3K27ac is known as an active enhancer mark because it is connected to greater transcriptional activation. Both the proximal and distal areas of the transcription start site include H3K27ac [8]. The H3K27ac mark we identified in the 51 amino acid aligned segment of KAT2A suggests that interaction of Orf8 at precisely this spot could disrupt KAT2A transcriptional function. We conclude that the 51 amino acid alignment of Human KAT2A Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein we identified suggests a significant effect of Orf8 on KAT2A. Orf8 may interfere with KAT2A gene transcription and disrupt the host cell’s ability to regulate gene expression and respond to SARS-CoV-2 infection effectively. Since transcription and translation are upregulated in cancer cells, Orf8 could be a cancer treatment [9]. A small molecule that fits into the open indentation at the site of alignment of Orf8 and KAT2A (Figure 3) might also derange KAT2A gene transcription. Table Table 1. Pymol performed 5 cycles of calculations on 65 aligned atoms of Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 Å for 51 atoms. MatchAlign: score 44.605 ExecutiveAlign: 65 atoms aligned. ExecutiveRMS: 4 atoms rejected during cycle 1 (RMSD=2.05). ExecutiveRMS: 3 atoms rejected during cycle 2 (RMSD=1.59). ExecutiveRMS: 3 atoms rejected during cycle 3 (RMSD=1.30). ExecutiveRMS: 2 atoms rejected during cycle 4 (RMSD=1.12). ExecutiveRMS: 2 atoms rejected during cycle 5 (RMSD=1.05). Executive: RMSD = 0.975 (51 to 51 atoms) References [1] Leslie M, Altounian V, Smith C (2022) A viral arsenal: SARS-CoV-2 wields versatile proteins to foil our immune system’s counterattack. Science 378 , 129-131. [2] Kee J, Thudium S, Renner DM, Glastad K, Palozola K, Zhang Z, Li Y, Lan Y, Cesare J, Poleshko A, Kiseleva AA, Truitt R, Cardenas-Diaz FL, Zhang X, Xie X, Kotton DN, Alysandratos KD, Epstein JA, Shi PY, Yang W, Morrisey E, Garcia BA, Berger SL, Weiss SR, Korb E (2022) SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. Nature 610 , 381-388. [3] Thomann L, Thiel V (2022) SARS-CoV-2 mimics a host protein to bypass defences. Nature 610 , 262-263. [4] Schuetz A, Bernstein G, Dong A, Antoshenko T, Wu H, Loppnau P, Bochkarev A, Plotnikov AN (2007) Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A. Proteins 68 , 403-407. [5] Chen X, Zhou Z, Huang C, Zhou Z, Kang S, Huang Z, Jiang G, Hong Z, Chen Q, Yang M, He S, Liu S, Chen J, Li K, Li X, Liao J, Chen J, Chen S (2021) Crystal Structures of Bat and Human Coronavirus ORF8 Protein Ig-Like Domain Provide Insights Into the Diversity of Immune Responses. Front Immunol 12 , 807134. [6] Valcarcel A, Bensussen A, Álvarez-Buylla ER, Díaz J (2021) Structural analysis of SARS-CoV-2 ORF8 protein: pathogenic and therapeutic implications. Frontiers in genetics 12 , 693227. [7] Wang Y, Wu H, Cai Y (2018) A benchmark study of sequence alignment methods for protein clustering. BMC Bioinformatics 19 , 529. [8] Beacon TH, Delcuve GP, López C, Nardocci G, Kovalchuk I, van Wijnen AJ, Davie JR (2021) The dynamic broad epigenetic (H3K4me3, H3K27ac) domain as a mark of essential genes. Clinical epigenetics 13 , 1-17. [9] Laham-Karam N, Pinto GP, Poso A, Kokkonen P (2020) Transcription and Translation Inhibitors in Cancer Treatment. Front Chem 8 , 276. Declarations Funding sources: none Conflicts of interest: none All data publicly available from RCSB Protein Data Bank Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-2235254","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":149552845,"identity":"0d8c550e-952c-4991-a262-0fc983e43230","order_by":0,"name":"Steven Lehrer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/ElEQVRIiWNgGAWjYPACCwYDEPWxAUQyNh7Aq5gNTEqAtTDObACyGBgbiNfCzAvWwsCAV4v8/OZjEh93SMiZSx8+9tl2h02dbvthoC01NtG4tBgcY0uTnHlGwtiyLy15du6ZNAmzM4lALcfSchtwaWHjMTbmbZNI3HCGx5g5t+2whNkBoBbGhsM4tci38X82/tsmUb/hDP9nZkuQlvMP8WthOMbD+JixTSLB4AwPMzMjSMsNArYYHEszfNjbJmG44QybMWNvW5rkthtAWxLw+EW++fCDAz/bbOQNzjA/ZgAy+M3Opz988KHGBrfDsIME0pSPglEwCkbBKEADAB7BXPt+oBdNAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-4850-094X","institution":"Fermata Pharma, Inc.","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Steven","middleName":"","lastName":"Lehrer","suffix":""},{"id":149552846,"identity":"0a79d087-aaf3-4124-bcfc-0b4e560f15f4","order_by":1,"name":"Peter Rheinstein","email":"","orcid":"","institution":"Severn Health Solutions","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Rheinstein","suffix":""}],"badges":[],"createdAt":"2022-11-03 17:13:51","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":true,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false,"coiExplicitlySet":false},"doi":"10.21203/rs.3.rs-2235254/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-2235254/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":29008250,"identity":"44fc939f-c9ff-4771-a38f-d798744b71bd","added_by":"auto","created_at":"2022-11-14 03:35:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":321352,"visible":true,"origin":"","legend":"\u003cp\u003eOrf8 aligned with KAT2A (Human GCN5 Acetyltransferase) (A) Black arrow points to closely aligned (RMSD = 0.975 Å) beta sheets of Orf8 (blue) and KAT2A (green). (B) Closeup of aligned beta sheets of Orf8 and KAT2A (center). Green upward pointing arrowhead indicates TYR 613 of KAT2A; directly underneath is VAL 117 of Orf8.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-2235254/v2/482953dd4128e486ce932b86.png"},{"id":29008251,"identity":"c74160a8-49d3-4aa1-869a-7a91c3ab2ec7","added_by":"auto","created_at":"2022-11-14 03:35:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":609781,"visible":true,"origin":"","legend":"\u003cp\u003eKAT2A in the UCSC Genome Browser. TYR 613 is in chromosome 17 position 17q12.21.3 42115759, exon 12 (arrows). This segment is highly conserved in 100 vertebrates, including the rhesus, mouse, dog, elephant, chicken, western clawed frog, and zebrafish. In addition, the segment is within an H3K27Ac mark (salmon color under down arrow) often found near regulatory elements.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-2235254/v2/d3704aef4f32bd5749f8cddc.png"},{"id":29008252,"identity":"f28e3f5c-4f2d-4486-a068-3eb75b5921b8","added_by":"auto","created_at":"2022-11-14 03:35:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":464736,"visible":true,"origin":"","legend":"\u003cp\u003eKAT2A with arrow pointing to location of alignment with Orf8. Note the open indentation in this position.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-2235254/v2/3ab7e7cc1f58907c1a20c13b.png"},{"id":29008253,"identity":"412a18d6-b64c-4664-92a1-6cf67fe5a102","added_by":"auto","created_at":"2022-11-14 03:35:12","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1370917,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-2235254/v2/0967d99f-7561-45b3-a36f-569520402a21.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eAlignment of human KAT2A (GCN5) Histone Acetyltransferase and SARS-CoV-2 Orf8 viral proteins\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe coronavirus SARS-CoV-2 has already claimed the lives of more than 6 million people, according to the World Health Organization, and the actual death toll may exceed 18 million. More and more people are avoiding severe cases of COVID-19 thanks to vaccines, medications, and immunity from prior infections. Yet the virus\u0026apos;s capacity to block the body\u0026apos;s immune response, made possible by its arsenal of proteins, is one factor in its propensity to spread [1].\u003c/p\u003e\n\u003cp\u003eThe SARS-CoV-2 virus, according to Kee et al., has evolved to mimic KAT2A (lysine acetyltransferase 2A, GCN5), one of the histone proteins that package DNA in the cell nucleus [2]. Gene transcription is deranged because of this mimicry, which reduces antiviral response. To create chromatin, DNA is wrapped around proteins like histone H3. Among other adjustments, the addition or removal of acetyl groups can modify how tightly chromatin is packed and influence how genes are expressed. An amino acid sequence known as the ARKS motif in H3 is modified by the enzyme KAT2A that adds acetyl groups and encourages gene transcription. Kee et al. found that the Orf8 protein from the SARS-CoV-2 virus also has an ARKS motif. KAT2A interacts with Orf8 via ARKS, which modifies it and may cause KAT2A destruction [3].\u003c/p\u003e\n\u003cp\u003eUsing structures from RCSB Protein Data Bank, we now report another way that Orf8 may interfere with KAT2A. 51 amino acids of Orf8 align closely with KAT2A and could adversely alter its activity.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe examined two RCSB Protein Data Bank molecules:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003e1Z4R. Human GCN5 (KAT2A) Histone Acetyltransferase [4].\u003c/li\u003e\n \u003cli\u003e7F5F. SARS-CoV-2 Orf8 S84 viral protein [5].\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe protein structures were superimposed and aligned on PYMOL v 2.5.0 with the Super command, which super aligns two protein selections. Super does a sequence-independent structure-based dynamic programming alignment (unlike the align command) followed by a series of refinement cycles intended to improve the fit by eliminating pairing with high relative variability. The Super command is more reliable than align for proteins with low sequence similarity.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003ePymol performed 5 cycles of calculations on 65 aligned atoms of Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 \u0026Aring; for 51 atoms (Table 1). Lower values of RMSD indicate that alignment is validated with higher accuracy. RMSD values of 1 \u0026Aring; or less indicate very good alignment. The two aligned molecules, Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein, are shown in figure 1. The 51-atom alignment is very good.\u003c/p\u003e\n\u003cp\u003eCloseup of aligned beta sheets of Orf8 and KAT2A (fig 1B) indicates TYR 613 of KAT2A is directly underneath VAL 117 of Orf8. According to the UCSC Genome Browser, TYR 613 is in chromosome 17 position 17q12.21.3 42115759, exon 12. This segment is highly conserved in 100 vertebrates, including the rhesus, mouse, dog, elephant, chicken, western clawed frog, and zebrafish. In addition, the segment is within an H3K27Ac mark often found near regulatory elements (fig 2).\u003c/p\u003e\n\u003cp\u003eFigure 3 shows KAT2A with arrow pointing to location of alignment with Orf8. Note the open indentation in this position.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eSARS-CoV-2 is quite good at blocking host interferon response. Interferons activate hundreds of genes that prevent viral propagation. SARS-CoV-2 proteins interfere with interferon response steps, sometimes with multiple proteins inhibiting the same step.\u003c/p\u003e\n\u003cp\u003eA protein of 121 amino acid residues and an N-terminal signal sequence are encoded by Orf8 during SARS-CoV-2 infection. Orf8 protein is a dimer that is joined covalently by disulfide links. Orf8 is not necessary for viral replication but does influence how the virus interacts with the host immune system, allowing immune evasion. Orf8 is intensely immunogenic. Persons recovering from SARS-CoV-2 infections have high levels of Orf8 antibodies [6].\u003c/p\u003e\n\u003cp\u003eThe protein structure alignment methods we describe are a powerful way to compare related protein sequences. They can be used to record a variety of information about the matched sequences, such as shared structural function or common evolutionary ancestry. Over the past few decades, protein sequence alignment analyses have become an essential stage in bioinformatics analytic research. Numerous protein databases with information on protein families were created using sequence alignments [7].\u003c/p\u003e\n\u003cp\u003eH3K27ac is an epigenetic modification to the DNA packaging protein histone H3. It is an indication that the lysine residue at the histone H3 protein\u0026apos;s N-terminal position 27 has been acetylated. H3K27ac is known as an active enhancer mark because it is connected to greater transcriptional activation. Both the proximal and distal areas of the transcription start site include H3K27ac [8]. The H3K27ac mark we identified in the 51 amino acid aligned segment of KAT2A suggests that interaction of Orf8 at precisely this spot could disrupt KAT2A transcriptional function.\u003c/p\u003e\n\u003cp\u003eWe conclude that the 51 amino acid alignment of Human KAT2A Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein we identified suggests a significant effect of Orf8 on KAT2A. Orf8 may interfere with KAT2A gene transcription and disrupt the host cell\u0026rsquo;s ability to regulate gene expression and respond to SARS-CoV-2 infection effectively. Since transcription and translation are upregulated in cancer cells, Orf8 could be a cancer treatment [9]. A small molecule that fits into the open indentation at the site of alignment of Orf8 and KAT2A (Figure 3) might also derange KAT2A gene transcription.\u003c/p\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1. Pymol performed 5 cycles of calculations on 65 aligned atoms of Human GCN5 Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 \u0026Aring; for 51 atoms.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;MatchAlign: score 44.605\u003cbr\u003e\u0026nbsp; ExecutiveAlign: 65 atoms aligned.\u003cbr\u003e\u0026nbsp; ExecutiveRMS: 4 atoms rejected during cycle 1 (RMSD=2.05).\u003cbr\u003e\u0026nbsp; ExecutiveRMS: 3 atoms rejected during cycle 2 (RMSD=1.59).\u003cbr\u003e\u0026nbsp; ExecutiveRMS: 3 atoms rejected during cycle 3 (RMSD=1.30).\u003cbr\u003e\u0026nbsp; ExecutiveRMS: 2 atoms rejected during cycle 4 (RMSD=1.12).\u003cbr\u003e\u0026nbsp; ExecutiveRMS: 2 atoms rejected during cycle 5 (RMSD=1.05).\u003cbr\u003e\u0026nbsp; Executive: RMSD = \u0026nbsp; \u0026nbsp;0.975 (51 to 51 atoms)\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e[1]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Leslie M, Altounian V, Smith C (2022) A viral arsenal: SARS-CoV-2 wields versatile proteins to foil our immune system\u0026rsquo;s counterattack. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e378\u003c/strong\u003e, 129-131.\u003c/p\u003e\n\u003cp\u003e[2]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Kee J, Thudium S, Renner DM, Glastad K, Palozola K, Zhang Z, Li Y, Lan Y, Cesare J, Poleshko A, Kiseleva AA, Truitt R, Cardenas-Diaz FL, Zhang X, Xie X, Kotton DN, Alysandratos KD, Epstein JA, Shi PY, Yang W, Morrisey E, Garcia BA, Berger SL, Weiss SR, Korb E (2022) SARS-CoV-2 disrupts host epigenetic regulation via histone mimicry. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e610\u003c/strong\u003e, 381-388.\u003c/p\u003e\n\u003cp\u003e[3]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Thomann L, Thiel V (2022) SARS-CoV-2 mimics a host protein to bypass defences. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e610\u003c/strong\u003e, 262-263.\u003c/p\u003e\n\u003cp\u003e[4]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Schuetz A, Bernstein G, Dong A, Antoshenko T, Wu H, Loppnau P, Bochkarev A, Plotnikov AN (2007) Crystal structure of a binary complex between human GCN5 histone acetyltransferase domain and acetyl coenzyme A. \u003cem\u003eProteins\u003c/em\u003e \u003cstrong\u003e68\u003c/strong\u003e, 403-407.\u003c/p\u003e\n\u003cp\u003e[5]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Chen X, Zhou Z, Huang C, Zhou Z, Kang S, Huang Z, Jiang G, Hong Z, Chen Q, Yang M, He S, Liu S, Chen J, Li K, Li X, Liao J, Chen J, Chen S (2021) Crystal Structures of Bat and Human Coronavirus ORF8 Protein Ig-Like Domain Provide Insights Into the Diversity of Immune Responses. \u003cem\u003eFront Immunol\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 807134.\u003c/p\u003e\n\u003cp\u003e[6]\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Valcarcel A, Bensussen A, \u0026Aacute;lvarez-Buylla ER, D\u0026iacute;az J (2021) Structural analysis of SARS-CoV-2 ORF8 protein: pathogenic and therapeutic implications. \u003cem\u003eFrontiers in genetics\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 693227.\u003c/p\u003e\n\u003cp\u003e[7]\u0026nbsp; 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Gene transcription is deranged because of this mimicry, which reduces antiviral response. An amino acid sequence known as the ARKS motif in histone H3 is modified by KAT2A, which adds acetyl groups and encourages gene transcription. The Orf8 protein from the SARS-CoV-2 virus also has an ARKS motif. KAT2A interacts with Orf8 via ARKS, which modifies it and may cause KAT2A destruction. Using structures from RCSB Protein Data Bank, we examined another way that Orf8 may interfere with KAT2A.\u003c/p\u003e\n\u003cp\u003eMethods: We analyzed two RCSB Protein Data Bank molecules: 1) 1Z4R. Human GCN5 (KAT2A) Histone Acetyltransferase. 2) 7F5F. SARS-CoV-2 Orf8 S84 viral protein. The protein structures were superimposed and aligned on PYMOL v 2.5.0 with the Super command, which super aligns two protein selections.\u003c/p\u003e\n\u003cp\u003eResults: Pymol performed 5 cycles of calculations on 65 aligned atoms of Human KAT2A (GCN5 Histone Acetyltransferase) and SARS-CoV-2 Orf8 S84 viral proteins, with a final root mean square deviation of atomic positions (RMSD) of 0.975 Angstrom for 51 atoms. Lower values of RMSD indicate that alignment is validated with higher accuracy. RMSD values of 1 Angstrom or less indicate very good alignment.\u003c/p\u003e\n\u003cp\u003eConclusion: the 51 amino acid alignment of Human KAT2A Histone Acetyltransferase and SARS-CoV-2 Orf8 S84 viral protein we identified suggests a significant effect of Orf8 on KAT2A. Orf8 may interfere with KAT2A gene transcription and disrupt host cell ability to regulate gene expression and respond to SARS-CoV-2 infection effectively. Since transcription and translation are upregulated in cancer cells, Orf8 could also be a cancer treatment.\u003c/p\u003e","manuscriptTitle":"Alignment of human KAT2A (GCN5) Histone Acetyltransferase and SARS-CoV-2 Orf8 viral proteins","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2022-11-14 03:34:56","doi":"10.21203/rs.3.rs-2235254/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2022-11-04 14:47:39","doi":"10.21203/rs.3.rs-2235254/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4d051c4c-616e-440c-a8d6-32fb81451b2f","owner":[],"postedDate":"November 14th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":16935332,"name":"Infectious Diseases"}],"tags":[],"updatedAt":"2022-11-04T14:47:39+00:00","versionOfRecord":[],"versionCreatedAt":"2022-11-14 03:34:56","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-2235254","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-2235254","identity":"rs-2235254","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}