Crystal Structure of the Nipah Virus Phosphoprotein Tetramerization Domain

Bruhn, Jessica F.; Barnett, Katherine C.; Bibby, Jaclyn; Thomas, Jens M. H.; Keegan, Ronan; Rigden, Daniel J.; Bornholdt, Zachary A.; Saphire, Erica Ollmann

doi:10.1128/jvi.02294-13

Cited by 75 publications

(88 citation statements)

References 49 publications

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“…This observation is in agreement with paramyxovirus P oligomerization domains, which also form long coiled coils and are highly thermally stable (Fig. 5B) (28,29).…”

Section: Vp35 Oligomerization Domain Structuresupporting

confidence: 88%

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

Bruhn

Kirchdoerfer

Urata

et al. 2017

J Virol

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Marburg virus (MARV) is a highly pathogenic filovirus that is classified in a genus distinct from that of Ebola virus (EBOV) (genera Marburgvirus and Ebolavirus, respectively). Both viruses produce a multifunctional protein termed VP35, which acts as a polymerase cofactor, a viral protein chaperone, and an antagonist of the innate immune response. VP35 contains a central oligomerization domain with a predicted coiled-coil motif. This domain has been shown to be essential for RNA polymerase function. Here we present crystal structures of the MARV VP35 oligomerization domain. These structures and accompanying biophysical characterization suggest that MARV VP35 is a trimer. In contrast, EBOV VP35 is likely a tetramer in solution. Differences in the oligomeric state of this protein may explain mechanistic differences in replication and immune evasion observed for MARV and EBOV.IMPORTANCE Marburg virus can cause severe disease, with up to 90% human lethality. Its genome is concise, only producing seven proteins. One of the proteins, VP35, is essential for replication of the viral genome and for evasion of host immune responses. VP35 oligomerizes (self-assembles) in order to function, yet the structure by which it assembles has not been visualized. Here we present two crystal structures of this oligomerization domain. In both structures, three copies of VP35 twist about each other to form a coiled coil. This trimeric assembly is in contrast to tetrameric predictions for VP35 of Ebola virus and to known structures of homologous proteins in the measles, mumps, and Nipah viruses. Distinct oligomeric states of the Marburg and Ebola virus VP35 proteins may explain differences between them in polymerase function and immune evasion. These findings may provide a more accurate understanding of the mechanisms governing VP35's functions and inform the design of therapeutics. KEYWORDS VP35, filovirus, RNA-dependent RNA polymerase, phosphoprotein, coiled coil, oligomerization, Marburg virus, Ebola virus, X-ray crystallography M arburg virus (MARV) can cause severe hemorrhagic fever in humans with high case fatality rates. Though less well known than its relative Ebola virus (EBOV), MARV was the first filovirus identified. MARV has caused sporadic outbreaks since its identification in 1968, including the 1998 to 2000 outbreak in the Democratic Republic of the Congo, which occurred with 83% lethality, and the 2004 to 2005 outbreak in Angola, which occurred with 90% lethality (1). Currently, there are no approved vaccines or therapeutics available to treat individuals infected with MARV. Despite sharing ϳ50% nucleotide sequence identity, MARV and EBOV have several striking functional differences. MARV does not produce sGP or ssGP protein and does not require VP30 for transcription. MARV and EBOV also exhibit differences in their immune evasion strategies (2).

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“…This observation is in agreement with paramyxovirus P oligomerization domains, which also form long coiled coils and are highly thermally stable (Fig. 5B) (28,29).…”

Section: Vp35 Oligomerization Domain Structuresupporting

confidence: 88%

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

Bruhn

Kirchdoerfer

Urata

et al. 2017

J Virol

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“…(A) A water-filled pocket was observed in the center of the NiV P coiled-coil domain toward its N terminus (PDB: 4N5B) (Bruhn et al, 2014). This water pocket is mediated by glycine 519 facing the interior of the coil, which creates empty space.…”

Section: Figure 2 the N-terminal Water Pocketmentioning

confidence: 99%

“…P also contains a central multimerization domain termed the PMD (P multimerization domain). Two crystal structures of this domain have been determined, both of which show that this domain is composed of a long, parallel, tetrameric coiled coil with an a-helical cap structure (Figures 1B and 1C) (Bruhn et al, 2014). This oligomerization domain has been shown to be essential for polymerase function in related viruses (Chen et al, 2006;Moller et al, 2005;Schneider et al, 2004) and was shown to be the L binding site for Sendai virus (SeV), a related paramyxovirus (Bowman et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

A Conserved Basic Patch and Central Kink in the Nipah Virus Phosphoprotein Multimerization Domain Are Essential for Polymerase Function

et al. 2019

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Graphical AbstractHighlights d A basic patch in the NiV phosphoprotein is essential for polymerase function d The central kink in the NiV phosphoprotein is essential for polymerase function d The basic patch and central kink are conserved in Nipah, mumps, and measles viruses SUMMARY Nipah virus is a highly lethal zoonotic pathogen found in Southeast Asia that has caused human encephalitis outbreaks with 40%-70% mortality. NiV encodes its own RNA-dependent RNA polymerase within the large protein, L. Efficient polymerase activity requires the phosphoprotein, P, which tethers L to its template, the viral nucleocapsid. P is a multifunctional protein with modular domains. The central P multimerization domain is composed of a long, tetrameric coiled coil. We investigated the importance of structural features found in this domain for polymerase function using a newly constructed NiV bicistronic minigenome assay. We identified a conserved basic patch and central kink in the coiled coil that are important for polymerase function, with R555 being absolutely essential. This basic patch and central kink are conserved in the related human pathogens measles and mumps viruses, suggesting that this mechanism may be conserved.

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“…The P gene produces non-structural accessory proteins known as C, V and W. NiV does not have the hemagglutinin and neuraminidase proteins as other Paramyxoviruses. 20,21 The viral matrix protein (M) of the plasma membrane mediates the contact between the ribonucleoprotein (RNP) complex and the surface glycoprotein, virus particle formation and budding. Replication occurs in cytoplasm.…”

Section: Properties Of Nipah Virusmentioning

confidence: 99%

Nipah virus in India: past, present and future

Prarthana¹

2018

Int J Community Med Public Health

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Nipah virus (NiV) is one of the emerging highly pathogenic virus. Like Ebola and Zika viruses, NiV too is threatening the integrity of the mankind. The family Paramyxoviruses has been traditionally associated with a group of viruses with narrow host range and typically causes outbreaks with low mortality rates. But with the emergence of highly pathogenic Hendra virus and closely related NiV, they have evolved as a cause of fatal encephalitis across broad range of vertebrate species including humans. The natural reservoir of NiV is Pteropus bat, which is apparently distributed all over the South East Asia. The bat population from North East to North West states in India have NiV antibodies which mean there is active NiV infection among Indian bats. As NiV is associated with high morbidity and mortality they pose a risk from natural outbreaks, laboratory accidents or deliberate misuse. The development of effective prevention and treatment strategies is very crucial. Preparedness, surveillance, constant vigil needs to be carried out continuously in the country. The present outbreak in India after nearly eleven years with a high case fatality rate indicate that there is a total lack of health care systems preparedness and surveillance strategy. The anthropogenic and environmental changes occurring due to rapid urbanization and massive deforestation has made India now even more vulnerable for such recurrent outbreaks. This review highlights the changing trend of the NiV outbreaks in the past and the current outbreak in India.

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Crystal Structure of the Nipah Virus Phosphoprotein Tetramerization Domain

Cited by 75 publications

References 49 publications

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

Crystal Structure of the Marburg Virus VP35 Oligomerization Domain

A Conserved Basic Patch and Central Kink in the Nipah Virus Phosphoprotein Multimerization Domain Are Essential for Polymerase Function

Nipah virus in India: past, present and future

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