6tzc | pdb_00006tzc
Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin
Structural highlights
Function[MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides. [BECN1_PIG] Plays a central role in autophagy. Acts as core subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate; different complex forms are believed to play a role in multiple membrane trafficking pathways: PI3KC3-C1 is involved in initiation of autophagosomes and PI3KC3-C2 in maturation of autophagosomes and endocytosis. Involved in regulation of degradative endocytic trafficking and required for the abcission step in cytokinesis, probably in the context of PI3KC3-C2. Essential for the formation of PI3KC3-C2 but not PI3KC3-C1 PI3K complex forms. Involved in endocytosis. May play a role in antiviral host defense (By similarity).[UniProtKB:O88597][UniProtKB:Q14457][UniProtKB:Q91XJ1] Beclin-1-C 35 kDa localized to mitochondria can promote apoptosis; it induces the mitochondrial translocation of BAX and the release of proapoptotic factors.[UniProtKB:O88597][UniProtKB:Q14457] [ARBH_ASFB7] Suppresses apoptosis in host cell and thus facilitates production of progeny virions (PubMed:9123849, PubMed:18329683). Has the ability to potentially bind to all the members of the proapoptotic Bcl-2 family (PubMed:28053104, PubMed:18329683).[1] [2] [3] Publication Abstract from PubMedSubversion of programmed cell death-based host defence systems is a prominent feature of infections by large DNA viruses. African swine fever virus (ASFV) is a large DNA virus and sole member of the Asfarviridae family that harbours the B-cell lymphoma 2 or Bcl-2 homolog A179L. A179L has been shown to bind to a range of cell death-inducing host proteins, including pro-apoptotic Bcl-2 proteins as well as the autophagy regulator Beclin. Here we report the crystal structure of A179L bound to the Beclin BH3 motif. A179L engages Beclin using the same canonical ligand-binding groove that is utilized to bind to pro-apoptotic Bcl-2 proteins. The mode of binding of Beclin to A179L mirrors that of Beclin binding to human Bcl-2 and Bcl-xL as well as murine gamma-herpesvirus 68. The introduction of bulky hydrophobic residues into the A179L ligand-binding groove via site-directed mutagenesis ablates binding of Beclin to A179L, leading to a loss of the ability of A179L to modulate autophagosome formation in Vero cells during starvation. Our findings provide a mechanistic understanding for the potent autophagy inhibitory activity of A179L and serve as a platform for more detailed investigations into the role of autophagy during ASFV infection. Crystal Structure of African Swine Fever Virus A179L with the Autophagy Regulator Beclin.,Banjara S, Shimmon GL, Dixon LK, Netherton CL, Hinds MG, Kvansakul M Viruses. 2019 Aug 27;11(9). pii: v11090789. doi: 10.3390/v11090789. PMID:31461953[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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