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Article

Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35

1
Department of Biochemistry & Biophysics, College of Science, Corvallis, OR 97331, USA
2
NMR Facility, Oregon State University, Corvallis, OR 97331, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Nathalie Sibille, Sonia Longhi and Carine Van Heijenoort
Biomolecules 2021, 11(11), 1603; https://doi.org/10.3390/biom11111603
Received: 24 September 2021 / Revised: 25 October 2021 / Accepted: 26 October 2021 / Published: 29 October 2021
The human parainfluenza virus 3 (HPIV3) poses a risk for pneumonia development in young children and immunocompromised patients. To investigate mechanisms of HPIV3 pathogenesis, we characterized the association state and host protein interactions of HPIV3 phosphoprotein (HPIV3 P), an indispensable viral polymerase cofactor. Sequence analysis and homology modeling predict that HPIV3 P possesses a long, disordered N-terminal tail (PTAIL) a coiled-coil multimerization domain (PMD), similar to the well-characterized paramyxovirus phosphoproteins from measles and Sendai viruses. Using a recombinantly expressed and purified construct of PMD and PTAIL, we show that HPIV3 P in solution is primarily an alpha-helical tetramer that is stable up to 60 °C. Pulldown and isothermal titration calorimetry experiments revealed that HPIV3 P binds the host hub protein LC8, and turbidity experiments demonstrated a new role for LC8 in increasing the solubility of HPIV3 P in the presence of crowding agents such as RNA. For comparison, we show that the multimerization domain of the Zaire Ebola virus phosphoprotein VP35 is also a tetramer and binds LC8 but with significantly higher affinity. Comparative analysis of the domain architecture of various virus phosphoproteins in the order Mononegavirales show multiple predicted and verified LC8 binding motifs, suggesting its prevalence and importance in regulating viral phosphoprotein structures. Our work provides evidence for LC8 binding to phosphoproteins with multiple association states, either tetrameric, as in the HPIV3 and Ebola phosphoproteins shown here, or dimeric as in rabies virus phosphoprotein. Taken together the data suggest that the association states of a virus-specific phosphoprotein and the complex formed by binding of the phosphoprotein to host LC8 are important regulators of viral function. View Full-Text
Keywords: HPIV3; EBOV; phosphoprotein; intrinsically disordered proteins; VP35; LC8; aggregation; host-pathogen interactions; RNA HPIV3; EBOV; phosphoprotein; intrinsically disordered proteins; VP35; LC8; aggregation; host-pathogen interactions; RNA
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MDPI and ACS Style

Rodriguez Galvan, J.; Donner, B.; Veseley, C.H.; Reardon, P.; Forsythe, H.M.; Howe, J.; Fujimura, G.; Barbar, E. Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35. Biomolecules 2021, 11, 1603. https://doi.org/10.3390/biom11111603

AMA Style

Rodriguez Galvan J, Donner B, Veseley CH, Reardon P, Forsythe HM, Howe J, Fujimura G, Barbar E. Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35. Biomolecules. 2021; 11(11):1603. https://doi.org/10.3390/biom11111603

Chicago/Turabian Style

Rodriguez Galvan, Joaquin, Brianna Donner, Cat Hoang Veseley, Patrick Reardon, Heather M. Forsythe, Jesse Howe, Gretchen Fujimura, and Elisar Barbar. 2021. "Human Parainfluenza Virus 3 Phosphoprotein Is a Tetramer and Shares Structural and Interaction Features with Ebola Phosphoprotein VP35" Biomolecules 11, no. 11: 1603. https://doi.org/10.3390/biom11111603

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