Structural highlights
Function
[L_HMPVC] Displays RNA-directed RNA polymerase, mRNA guanylyl transferase, mRNA (guanine-N(7)-)-methyltransferase and poly(A) synthetase activities. The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). Functions either as transcriptase or as replicase. The transcriptase synthesizes subsequently the subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The replicase mode is dependent on intracellular protein N concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals (By similarity). [PHOSP_HMPVC] Acts as a cofactor that serves both to stabilize the protein L and to place the polymerase complex on the N:RNA template.
Publication Abstract from PubMed
Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elder adults(1). Neither a vaccine nor an effective antiviral therapy exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the nucleoprotein-RNA (N-RNA) template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase (PRNTase) and cap-specific methyltransferases (MTases) activities(2,3). How P interacts with L and mediates association with the free form of N and with the ribonucleoprotein (RNP) is not clear for HMPV or other prominent human pathogens including measles, Ebola and rabies viruses. Here, we report a cryo-EM reconstruction showing the ring-shaped structure of the polymerase and capping domains of HMPV L, bound with a tetramer of P. The connector and MTase domains are mobile with respect to the core. The putative priming loop important for initiation of RNA synthesis is fully retracted, leaving space in the active-site cavity for RNA elongation. P interacts extensively with the N-terminal region of L, burying more than 4,016 A(2) of molecular surface area in the interface. Two of the four helices forming the coiled-coil tetramerization domain of P, and long C-terminal extensions projecting from these two helices, wrap around the L protein like tentacles. The structural versatility of the four P protomers, which are largely disordered in their free state, demonstrates an example of a "folding-upon-partner-binding" mechanism for carrying-out P adaptor functions. The structure shows that P has the potential to modulate multiple functions of L and should accelerate the design of specific antiviral drugs.
Structure of the human metapneumovirus polymerase phosphoprotein complex.,Pan J, Qian X, Lattmann S, El Sahili A, Yeo TH, Jia H, Cressey T, Ludeke B, Noton S, Kalocsay M, Fearns R, Lescar J Nature. 2019 Nov 7. pii: 10.1038/s41586-019-1759-1. doi:, 10.1038/s41586-019-1759-1. PMID:31698413[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pan J, Qian X, Lattmann S, El Sahili A, Yeo TH, Jia H, Cressey T, Ludeke B, Noton S, Kalocsay M, Fearns R, Lescar J. Structure of the human metapneumovirus polymerase phosphoprotein complex. Nature. 2019 Nov 7. pii: 10.1038/s41586-019-1759-1. doi:, 10.1038/s41586-019-1759-1. PMID:31698413 doi:http://dx.doi.org/10.1038/s41586-019-1759-1
