2023-04-18 07:33:11
The alphavirus superfamily includes many pathogens including the Chikungunya virus. Viral genome replication is orchestrated by a complex of four viral proteins located in basket-shaped organelles derived from the host cell’s plasma membrane.
One of these four proteins, called nsP1, forms a porous dodecameric structure that serves as a platform for the assembly of the replication complex. But nsP1 has an additional enzymatic function which is to add a “cap” to the 5′ end of viral RNAs as they are synthesized and extruded from the organelle. This cap protects the viral RNA from the host cell’s defense system.
The establishment of this cap by the nsP1 protein is done according to an original mechanism and differs from that used for cellular RNA, making this protein a potential target for future antivirals. In particular, the different steps are carried out in the reverse order of the cellular mechanisms. Until now the molecular basis of this mechanism has remained elusive.
Scientists performed biochemical analyzes coupled with cryo-electron microscopy studies to provide high-resolution information on how nsP1 puts this cap on.
The details of substrate binding in each of the 12 pockets of the dodecameric structure explain, on a molecular level, why the steps of the establishment of the cap are reversed compared to the cellular enzymes. Surprisingly, the scientists also demonstrated that the nsP1 protein is able to remove the cap from RNA. This discovery raises many questions about the role of this new mechanism but can be related to the recent observation of viral RNA without a cap during the release of Chikungunya virions.
The structures obtained by cryomicroscopy also provide numerous observations on the dynamics of the placement of the rotator cuff. These details can be used to search for new inhibitors against alphavirus infection.
Figure : Structure of the dodecameric protein of the nsP1 protein (yellow) with the substrates (green and blue) on each of the 12 active enzymatic sites and detail of one of the sites.
To know more :
Structural basis and dynamics of Chikungunya alphavirus RNA capping by nsP1 capping pores.
R.Jones, M.Hons, N.Rabah, N.Zamarreño, R.Arranz & J.Reguera.
PNAS, March 13, 2023. TWO: https://doi.org/10.1073/pnas.2213934120
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