2hn8
Structural characterization and oligomerization of PB1-F2, a pro-apoptotic influenza A virus protein
Structural highlights
FunctionPB1F2_I34A1 Plays an important role in promoting lung pathology in both primary viral infection and secondary bacterial infection. Promotes alteration of mitochondrial morphology, dissipation of mitochondrial membrane potential, and cell death. Alternatively, inhibits the production of interferon in the infected cell at the level of host mitochondrial antiviral signaling MAVS. Its level of expression differs greatly depending on which cell type is infected, in a manner that is independent of the levels of expression of other viral proteins. Monocytic cells are more affected than epithelial cells. Seems to disable virus-infected monocytes or other host innate immune cells. May also act in trans: extracellular PB1-F2 released by infected cells could potentially inactivate hosts cell recruitment to the site of infection. During early stage of infection, may predispose the mitochondria to permeability transition through interaction with human SLC25A6/ANT3 and VDAC1. These proteins participate in the formation of the permeability transition pore complex (PTPC) responsible of the release of mitochondrial products that triggers apoptosis.[1] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedRecently, a novel 87-amino acid influenza A virus protein with proapoptotic properties, PB1-F2, has been reported that originates from an alternative reading frame in the PB1 polymerase gene and is encoded in most known human influenza A virus isolates. Here we characterize the molecular structure of a biologically active synthetic version of the protein (sPB1-F2). Western blot analysis, chemical cross-linking, and NMR spectroscopy afforded direct evidence of the inherent tendency of sPB1-F2 to undergo oligomerization mediated by two distinct domains located in the N and C termini, respectively. CD and (1)H NMR spectroscopic analyses indicate that the stability of structured regions in the molecule clearly depends upon the hydrophobicity of the solvent. In aqueous solutions, the behavior of sPB1-F2 is typical of a largely random coil peptide that, however, adopts alpha-helical structure upon the addition of membrane mimetics. (1)H NMR analysis of three overlapping peptides afforded, for the first time, direct experimental evidence of the presence of a C-terminal region with strong alpha-helical propensity comprising amino acid residues Ile(55)-Lys(85) connected via an essentially random coil structure to a much weaker helix-like region, located in the N terminus between residues Trp(9) and Lys(20). The C-terminal helix is not a true amphipathic helix and is more compact than previously predicted. It corresponds to a positively charged region previously shown to include the mitochondrial targeting sequence of PB1-F2. The consequences of the strong oligomerization and helical propensities of the molecule are discussed and used to formulate a hypothetical model of its interaction with the mitochondrial membrane. Structural characterization and oligomerization of PB1-F2, a proapoptotic influenza A virus protein.,Bruns K, Studtrucker N, Sharma A, Fossen T, Mitzner D, Eissmann A, Tessmer U, Roder R, Henklein P, Wray V, Schubert U J Biol Chem. 2007 Jan 5;282(1):353-63. Epub 2006 Oct 19. PMID:17052982[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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