A bioinformatic analysis of the mononegavirales transcription/replication complex through the development of the Dissic pipeline
Cleveland, Sean Bruce.
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The viral members of the Order Mononegavirales are responsible for numerous diseases with high mortality and few if any treatments. Unfortunately, knowledge of these viruses is limited. Attempts to study the structure of the replication/transcription complex of these viruses using physical methods like X-ray crystallography and NMR spectroscopy have been largely unsuccessful due to the large size of this complex, as well as the amount of disorder these proteins show when isolated. The goal of this Bioinformatic study is to investigate sequence conservation in relation to evolutionary function/structure of the nucleoprotein (N), large subunit polymerase protein (L) and phosphoprotein (P) of the Order Mononegavirales. In the combined analysis of 63 representative viruses from the four viral families (Paramyxoviridae, Rhabdoviridae, Filoviridae, and Bornaviridae) were predicted using a developed Disorder, Intra-residue contact and Compensatory mutation Correlator, (DisICC) pipeline. The N protein results indicate conservation for disorder in the C-terminus region of the N viral proteins important for interacting with P and L during transcription and replication. Portions of the N-terminus are responsible for N:N stability with interactions identified by the presence or lack of co-evolving intra-protein contact predictions. Correlations between location and conservation of predicted regions reveal strong divisions between families while highlighting conservation within individual families in L. Suggesting L Domains are conserved across the Order with strong intra-sequence pressures for conservation, while hinge regions lack these pressures. Conserved disorder is reported for: the amino-terminal of L for L-L complex formation across all families, Domain V for capping activity across Paramyxovirinae and Vesiculovirus, and Domain VI for cap methylation is conserved across Paramyxovirinae, Rubulaviruses, Avulaviruses, Ferlavirus and Morbilliviruses. The P sequences show a strong conservation of disorder within viral families that corresponds to their binding Domains with little intra-sequence pressure. Validation of these predictions by current experimental and structural information illustrates the benefits of the DisICC pipeline for characterizing protein disorder and intra-residue contact that can reveal likely residues as disruption targets in these viruses that are infectious to humans.