Structural Insight into KsBcl-2 Mediated Apoptosis Inhibition by Kaposi Sarcoma Associated Herpes Virus
journal contributionposted on 2022-05-10, 01:25 authored by Chathura SuraweeraChathura Suraweera, MG Hinds, Marc KvansakulMarc Kvansakul
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 gammaherpesvirinae, 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.
This research was funded by La Trobe University (Scholarship to C.D.S.).
Article NumberARTN 738
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Science & TechnologyLife Sciences & BiomedicineVirologyBcl-2apoptosisBidKaposi Sarcoma HerpesvirusherpesvirusesX-ray crystallographyEPSTEIN-BARR-VIRUSBCL-2 HOMOLOGVIRAL BCL-2PROSURVIVAL BCL-2BH3 DOMAINSCELL-DEATHPROTEINSMCL-1HUMAN-HERPESVIRUS-8BAXApoptosisApoptosis Regulatory ProteinsHerpesvirus 8, HumanHumansProto-Oncogene Proteins c-bcl-2Sarcoma, KaposiViral Proteins