title: The flexible C-terminal arm of the Lassa arenavirus Z-protein mediates interactions with multiple binding partners.
abstract: The arenavirus genome encodes for a Z-protein, which contains a RING domain that coordinates two zinc ions, and has been identified as having several functional roles at various stages of the virus life cycle. Z-protein binds to multiple host proteins and has been directly implicated in the promotion of viral budding, repression of mRNA translation, and apoptosis of infected cells. Using homology models of the Z-protein from Lassa strain arenavirus, replica exchange molecular dynamics (MD) was used to refine the structures, which were then subsequently clustered. Population-weighted ensembles of low-energy cluster representatives were predicted based upon optimal agreement of the chemical shifts computed with the SPARTA program with the experimental NMR chemical shifts. A member of the refined ensemble was identified to be a potential binder of budding factor Tsg101 based on its correspondence to the structure of the HIV-1 Gag late domain when bound to Tsg101. Members of these ensembles were docked against the crystal structure of human eIF4E translation initiation factor. Two plausible binding modes emerged based upon their agreement with experimental observation, favorable interaction energies and stability during MD trajectories. Mutations to Z are proposed that would either inhibit both binding mechanisms or selectively inhibit only one mode. The C-terminal domain conformation of the most populated member of the representative ensemble shielded protein-binding recognition motifs for Tsg101 and eIF4E and represents the most populated state free in solution. We propose that C-terminal flexibility is key for mediating the different functional states of the Z-protein.
authors.affiliation: Department of Chemistry and Program in Biophysics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Eric R
authors.initials: ER
authors.lastname: May
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
authors.forename: Aristotle M
authors.initials: AM
authors.lastname: Mannan
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D056827:Endosomal Sorting Complexes Required for Transport / Q000737:chemistry / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000737:chemistry / Q000378:metabolism; D007836:Lassa virus / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D054829:RING Finger Domains; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000737:chemistry* / Q000378:metabolism; D000099177:Tsg101 Protein
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D039561:Eukaryotic Initiation Factor-4E; D050505:Mutant Proteins; D014157:Transcription Factors; D014764:Viral Proteins; D015032:Zinc; D000099177:Tsg101 Protein; C017800:zinc-binding protein