Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus
Numerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a memb...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/4/738 |
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| author | Chathura D. Suraweera Mark G. Hinds Marc Kvansakul |
| author_facet | Chathura D. Suraweera Mark G. Hinds Marc Kvansakul |
| author_sort | Chathura D. Suraweera |
| collection | DOAJ |
| description | Numerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a member of the <i>gammaherpesvirinae</i>, has been shown to encode for KsBcl-2, a potent inhibitor of Bcl-2 mediated apoptosis. KsBcl-2 acts by directly engaging host pro-apoptotic Bcl-2 proteins including Bak, Bax and Bok, the BH3-only proteins; Bim, Bid, Bik, Hrk, Noxa and Puma. Here we determined the crystal structures of KsBcl-2 bound to the BH3 motif of pro-apoptotic proteins Bid and Puma. The structures reveal that KsBcl-2 engages pro-apoptotic BH3 motif peptides using the canonical ligand binding groove. Thus, the presence of the readily identifiable conserved BH1 motif sequence “NWGR” of KsBcl-2, as well as highly conserved Arg residue (R86) forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for KSHV mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways. |
| first_indexed | 2024-03-09T12:53:01Z |
| format | Article |
| id | doaj.art-8540082fd0e54c4992c5b85527b390df |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T12:53:01Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-8540082fd0e54c4992c5b85527b390df2023-11-30T22:03:37ZengMDPI AGViruses1999-49152022-03-0114473810.3390/v14040738Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes VirusChathura D. Suraweera0Mark G. Hinds1Marc Kvansakul2Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, AustraliaBio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Parkville, VIC 3052, AustraliaDepartment of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086, AustraliaNumerous large DNA viruses have evolved sophisticated countermeasures to hijack the premature programmed cell death of host cells post-infection, including the expression of proteins homologous in sequence, structure, or function to cellular Bcl-2 proteins. Kaposi sarcoma herpes virus (KSHV), a member of the <i>gammaherpesvirinae</i>, has been shown to encode for KsBcl-2, a potent inhibitor of Bcl-2 mediated apoptosis. KsBcl-2 acts by directly engaging host pro-apoptotic Bcl-2 proteins including Bak, Bax and Bok, the BH3-only proteins; Bim, Bid, Bik, Hrk, Noxa and Puma. Here we determined the crystal structures of KsBcl-2 bound to the BH3 motif of pro-apoptotic proteins Bid and Puma. The structures reveal that KsBcl-2 engages pro-apoptotic BH3 motif peptides using the canonical ligand binding groove. Thus, the presence of the readily identifiable conserved BH1 motif sequence “NWGR” of KsBcl-2, as well as highly conserved Arg residue (R86) forms an ionic interaction with the conserved Asp in the BH3 motif in a manner that mimics the canonical ionic interaction seen in host Bcl-2:BH3 motif complexes. These findings provide a structural basis for KSHV mediated inhibition of host cell apoptosis and reveal the flexibility of virus encoded Bcl-2 proteins to mimic key interactions from endogenous host signalling pathways.https://www.mdpi.com/1999-4915/14/4/738Bcl-2apoptosisBidKaposi Sarcoma HerpesvirusherpesvirusesX-ray crystallography |
| spellingShingle | Chathura D. Suraweera Mark G. Hinds Marc Kvansakul Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus Viruses Bcl-2 apoptosis Bid Kaposi Sarcoma Herpesvirus herpesviruses X-ray crystallography |
| title | Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus |
| title_full | Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus |
| title_fullStr | Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus |
| title_full_unstemmed | Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus |
| title_short | Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus |
| title_sort | structural insight into ksbcl 2 mediated apoptosis inhibition by kaposi sarcoma associated herpes virus |
| topic | Bcl-2 apoptosis Bid Kaposi Sarcoma Herpesvirus herpesviruses X-ray crystallography |
| url | https://www.mdpi.com/1999-4915/14/4/738 |
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