title: Evolution and structural organization of the C proteins of paramyxovirinae.
abstract: The phosphoprotein (P) gene of most Paramyxovirinae encodes several proteins in overlapping frames: P and V, which share a common N-terminus (PNT), and C, which overlaps PNT. Overlapping genes are of particular interest because they encode proteins originated de novo, some of which have unknown structural folds, challenging the notion that nature utilizes only a limited, well-mapped area of fold space. The C proteins cluster in three groups, comprising measles, Nipah, and Sendai virus. We predicted that all C proteins have a similar organization: a variable, disordered N-terminus and a conserved, α-helical C-terminus. We confirmed this predicted organization by biophysically characterizing recombinant C proteins from Tupaia paramyxovirus (measles group) and human parainfluenza virus 1 (Sendai group). We also found that the C of the measles and Nipah groups have statistically significant sequence similarity, indicating a common origin. Although the C of the Sendai group lack sequence similarity with them, we speculate that they also have a common origin, given their similar genomic location and structural organization. Since C is dispensable for viral replication, unlike PNT, we hypothesize that C may have originated de novo by overprinting PNT in the ancestor of Paramyxovirinae. Intriguingly, in measles virus and Nipah virus, PNT encodes STAT1-binding sites that overlap different regions of the C-terminus of C, indicating they have probably originated independently. This arrangement, in which the same genetic region encodes simultaneously a crucial functional motif (a STAT1-binding site) and a highly constrained region (the C-terminus of C), seems paradoxical, since it should severely reduce the ability of the virus to adapt. The fact that it originated twice suggests that it must be balanced by an evolutionary advantage, perhaps from reducing the size of the genetic region vulnerable to mutations.
authors.affiliation: Centers for Disease Control and Prevention, Viral Special Pathogens Branch, Atlanta, Georgia, United States of America.
authors.forename: Michael K
authors.initials: MK
authors.lastname: Lo
authors.affiliation: Division of Structural Biology, Oxford University, Oxford, United Kingdom.
authors.forename: Teit Max
authors.initials: TM
authors.lastname: Søgaard
authors.affiliation: Division of Structural Biology, Oxford University, Oxford, United Kingdom ; Department of Zoology, University of Oxford, Oxford, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Karlin
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019143:Evolution, Molecular; D008969:Molecular Sequence Data; D018098:Paramyxovirinae / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D016415:Sequence Alignment; D017421:Sequence Analysis; D012689:Sequence Homology, Nucleic Acid; D013045:Species Specificity; D014764:Viral Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; D014764:Viral Proteins