Ku, Bonsu Woo, Jae-Sung Liang, Chengyu Lee, Kwang-Hoon Hong, Hyang-Suk Xiaofei, E. Kim, Key-Sun Jung, Jae U. Oh, Byung-Ha 2024-01-21T00:00:40Z 2024-01-21T00:00:40Z 2021-09-03 2008-02 1553-7366 https://pubs.kist.re.kr/handle/201004/133773 All gammaherpesviruses express homologues of antiapoptotic B-cell lymphoma-2 ( BCL-2) to counter the clearance of infected cells by host antiviral defense machineries. To gain insights into the action mechanisms of these viral BCL-2 proteins, we carried out structural and biochemical analyses on the interactions of M11, a viral BCL-2 of murine gamma-herpesvirus 68, with a fragment of proautophagic Beclin1 and BCL- 2 homology 3 ( BH3) domain-containing peptides derived from an array of proapoptotic BCL- 2 family proteins. Mainly through hydrophobic interactions, M11 bound the BH3-like domain of Beclin1 with a dissociation constant of 40 nanomole, a markedly tighter affinity compared to the 1.7 micromolar binding affinity between cellular BCL- 2 and Beclin1. Consistently, M11 inhibited autophagy more efficiently than BCL- 2 in NIH3T3 cells. M11 also interacted tightly with a BH3 domain peptide of BAK and those of the upstream BH3- only proteins BIM, BID, BMF, PUMA, and Noxa, but weakly with that of BAX. These results collectively suggest that M11 potently inhibits Beclin1 in addition to broadly neutralizing the proapoptotic BCL- 2 family in a similar but distinctive way from cellular BCL- 2, and that the Beclin1- mediated autophagy may be a main target of the virus. English PUBLIC LIBRARY SCIENCE Structural and biochemical bases for the inhibition of autophagy and apoptosis by viral BCL-2 of murine gamma-herpesvirus 68 Article 10.1371/journal.ppat.0040025 1 PLOS PATHOGENS, v.4, no.2 PLOS PATHOGENS 4 2 N scie scopus 000255415900040 2-s2.0-40449127353 Microbiology Parasitology Virology Microbiology Parasitology Virology Article PEPTIDE COMPLEX CELL-DEATH IN-VIVO PROSURVIVAL BCL-2 CRYSTAL-STRUCTURE PROTEIN FAMILY VIRUS HOMOLOG BAX SUPPRESSOR