Functional and evolutionary insight from the crystal structure of rubella virus protein E1

DuBois, Rebecca M.; Vaney, M.C.; Tortorici, M. Alejandra; Kurdi, Rana Al; Barba-Spaeth, Giovanna; Krey, Thomas; Rey, F.A.

doi:10.1038/nature11741

Cited by 94 publications

(161 citation statements)

References 35 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…A chemically synthesized DNA fragment (GeneArt) containing the Zika sE sequence (amino acids 1-408) was cloned into the expression vector pT389 (ref. 31) that encodes the export signal sequence BIP, an enterokinase cleavage site and the strep-tag. Drosophila Schneider 2 (S2) cells were stably transfected using blasticidin for selection.…”

Section: Methodsmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

Self Cite

479

540

View full text Add to dashboard Cite

Zika virus (ZIKV) is an arthropod-borne enveloped virus belonging to the Flavivirus genus in the family Flaviviridae, which also includes the human pathogenic yellow fever, dengue, West Nile and tick-borne encephalitis viruses 1 . Flaviviruses have two structural glycoproteins, prM and E (for precursor membrane and envelope proteins, respectively), which form a heterodimer in the endoplasmic reticulum (ER) of the infected cell and drive the budding of spiky immature virions into the ER lumen. These particles transit through the cellular secretory pathway, during which the trans-Golgi-resident protease furin cleaves prM. This processing is required for infectivity, and results in the loss of a large fragment of prM and reorganization of E on the virion surface. The mature particles have a smooth aspect, with 90 E dimers organized with icosahedral symmetry in a 'herringbone' pattern 2,3 .Three-dimensional cryo-electron microscopy (cryo-EM) structures of the mature ZIKV particles have recently been reported to near atomic resolution (3.8 Å) 4,5 , showing that the virus has essentially the same organization as the other flaviviruses of known structure, such as dengue virus (DENV) 3 and West Nile virus 6,7 . The E protein is about 500 amino acids long, with the 400 N-terminal residues forming the ectodomain essentially folded as β-sheets with three domains, named I, II and III, aligned in a row with domain I at the centre. The conserved fusion loop is at the distal end of the rod in domain II, buried at the E dimer interface. At the C terminus, the E ectodomain is followed by the 'stem' , featuring two α-helices lying flat on the viral membrane (the stem helices), which link to two C-terminal transmembrane α-helices. The main distinguishing feature of the ZIKV virion is an insertion within a glycosylated loop of E (the '150' loop), which protrudes from the mature virion surface 4,5 .Flaviviruses have been grouped into serocomplexes based on cross-neutralization studies with polyclonal immune sera 8 . The E protein is the main target of neutralizing antibodies, and is also the viral fusogen; cleavage of prM allows E to respond to the endosomal pH by undergoing a large-scale conformational change that catalyses membrane fusion and releases the viral genome into the cyotosol. Loss of the precursor fragment of prM lets the E protein fluctuate from its tight packing at the surface of the virion, transiently exposing otherwise buried surfaces. One surface exposed by this 'breathing' is the fusionloop epitope (FLE), which is a dominant cross-reactive antigenic site 9 . Although antibodies to this site can protect by complement-mediated mechanisms, as shown in a mouse model for West Nile virus 10 , they are poorly neutralizing and lead to antibody-dependent enhancement 11-15 , thereby aggravating Flavivirus pathogenesis and complicating the development of safe and effective vaccines.We recently reported the functional and structural characterization of a panel of antibodies isolated from patients with dengue disease 13,16 . ...

show abstract

Section: Methodsmentioning

confidence: 99%

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Barba-Spaeth

Dejnirattisai

Rouvinski

et al. 2016

Nature

Self Cite

479

540

View full text Add to dashboard Cite

show abstract

“…The E1 glycoprotein of alphaviruses and RV (27,28) and the E glycoprotein of flaviviruses (29) have similar structures. This common surface glycoprotein motif suggests that these structures evolved from an ancestral structure (28) that can attach to potential host cells and initiate infection by fusion with the host cell.…”

Section: Probable Location Of the Glycoprotein-binding Region On The mentioning

confidence: 95%

Rubella virus capsid protein structure and its role in virus assembly and infection

Prasad

Willows

Fokine

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Rubella virus (RV) is a leading cause of birth defects due to infectious agents. When contracted during pregnancy, RV infection leads to severe damage in fetuses. Despite its medical importance, compared with the related alphaviruses, very little is known about the structure of RV. The RV capsid protein is an essential structural component of virions as well as a key factor in virus-host interactions. Here we describe three crystal structures of the structural domain of the RV capsid protein. The polypeptide fold of the RV capsid protomer has not been observed previously. Combining the atomic structure of the RV capsid protein with the cryoelectron tomograms of RV particles established a low-resolution structure of the virion. Mutational studies based on this structure confirmed the role of amino acid residues in the capsid that function in the assembly of infectious virions.X-ray crystallography | cryoelectron tomography | virology R ubella virus (RV) is the only member of the Rubivirus genus which, together with alphaviruses including Chikungunya virus, Sindbis virus, and Ross River virus, make up the family Togaviridae. RV is a human pathogen that causes "German measles," a relatively mild disease characterized by rashes and low-grade fever. However, due to its teratogenic properties, RV is a major threat to the fetus when infection occurs during the first trimester of pregnancy (1). Vaccination has been very successful in controlling RV infection; however, the virus is still endemic in many areas of the world (1, 2). RV is an enveloped virus with a 9.6-kb single-stranded, positive-sense RNA genome (1, 3). The virions have particle diameters ranging from 600 to 800 Å, with most of the spherical virions having a diameter of about 700 Å (4). RV contains three structural proteins, namely, the capsid protein (∼31 kDa) and the glycoproteins E1 (58 kDa) and E2 (42-47 kDa). The capsid protein interacts with the RNA genome and forms the nucleocapsid, which is surrounded by a lipid membrane upon which E1 and E2 are arranged. Two nonstructural proteins, p90 and p150, involved with virus replication, are also encoded by the virus (1).Alphaviruses and RV share a similar gene order and expression strategy (3) but differ from each other in that alphaviruses are icosahedral, their nucleocapsids assemble in the cytoplasm, and virions bud from the plasma membrane (5). In contrast, RV virions are pleomorphic and the nucleocapsid assembles on Golgi membranes followed by budding of the virus into this organelle (6). The pleomorphic nature of RV virions has been a limiting factor in determining the structure of the virus particles.As with all Togaviruses, the structural proteins of RV are synthesized as a polyprotein precursor in association with the endoplasmic reticulum in the host cell (7) (Fig. 1A). The polyprotein is cotranslationally cleaved by the host-cell signal peptidase but, unlike alphavirus capsid proteins, the RV capsid protein remains attached to the cytoplasmic side of the membrane by virtue of the hydrophobic E2 ...

show abstract

“…Se ha descrito que los bucles FL1 Y FL2 de E1-RV se unen a átomos de calcio, unión que se ha asociado con un mecanismo de fusión a la célula huésped mediada por calcio en el RV (32). La estructura del FL1 de E1-RV se da por una inserción de aminoácidos que no se encuentra en la E1-ZIKV (figuras [3][4][5].…”

Section: Discussionunclassified

“…Estas y otras comparaciones de las proteínas de fusión de membrana en alfavirus y algunos flavivirus, incluidos los DENV 1 a 4, el YFV y el WNV, todos con elementos estructurales de fusión muy conservados, revelan una posible selección evolutiva y funcional de este tipo de proteínas (32,36,37).…”

Section: Discussionunclassified

“…En color blanco, aparece el bucle FL2 en la proteína E1-ZIKV, homólogo putativo del bucle FL2 de E1-RV, el cual se definió desde el residuo Val 97 hasta el residuo Lys 110. En D. se detalla el sitio ocupado por el ión de calcio y los aminoácidos que participan en el sitio de unión (32). Con un punto central en blanco, se representa el calcio entre los bucles FL1 y FL2, localizado entre los residuos Asn 88 y Asp 136 (en color amarillo) de los bucles FL1 y FL2, respectivamente.…”

Section: Fl2 Fl1 Fl2unclassified

See 1 more Smart Citation

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

et al. 2016

View full text Add to dashboard Cite

: concepción y formulación de la hipótesis, planteamiento del objetivo y la pregunta de investigación, obtención de las estructuras moleculares, interpretación y discusión de los resultados Gladis Montoya: obtención de las estructuras moleculares Todos los autores participaron en el análisis comparativo de resultados y la escritura del manuscrito.Características de la estructura molecular de las proteínas E del virus del Zika y E1 del virus de la rubéola y posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso Introducción. El virus del Zika (ZIKV) es un flavivirus con envoltura, transmitido a los seres humanos principalmente por el vector Aedes aegypti. La infección por ZIKV se ha asociado con un gran neurotropismo y con efectos neuropáticos, como el síndrome de Guillain-Barré en el adulto y la microcefalia fetal y posnatal, así como con un síndrome de infección congénita similar al producido por el virus de la rubéola (RV).Objetivo. Comparar las estructuras moleculares de la proteína de envoltura E del virus del Zika (E-ZIKV) y de la E1 del virus de la rubéola (E1-RV), y plantear posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso asociadas con el ZIKV. Materiales y métodos. La secuencia de aminoácidos de la proteína E-ZIKV (PDB: 5iZ7) se alineó con la de la glucopreteína E1 del virus de la rubéola (PDB: 4ADG). Los elementos de la estructura secundaria se determinaron usando los programas Vector NTI Advance ® , DSSP y POSA, así como herramientas de gestión de datos (AlignX ® ). Uno de los criterios principales de comparación y alineación fue la asignación de residuos estructuralmente equivalentes, con más de 70 % de identidad.Resultados. La organización estructural de la proteína E-ZIKV (PDB: 5iZ7) fue similar a la de E1-RV (PDB: 4ADG) (70 a 80 % de identidad), y se observó una correspondencia con la estructura definida para las glucoproteínas de fusión de membrana de clase II de los virus con envoltura. E-ZIKV y E1-RV exhibieron elementos estructurales de fusión muy conservados en la región distal del dominio II, asociados con la unión a los receptores celulares de entrada del virus de la rubéola (glucoproteína de mielina del oligodendrocito, Myelin Oligodendrocyte Glycoprotein, MOG), y con los receptores celulares Axl del ZIKV y de otros flavivirus. Conclusión. La comparación de las proteínas E-ZIKV y E1-RV es un paso necesario hacia la definición de otros factores moleculares determinantes del neurotropismo y la patogenia del ZIKV, el cual puede contribuir a generar estrategias de diagnóstico, prevención y tratamiento de las complicaciones neurológicas inducidas por el ZIKV.Palabras clave: virus Zika; virus de la rubéola; estructura molecular; microcefalia; glucoproteína de la mielina del oligodendrocito. Materials and methods:The amino acid sequence of E-ZIKV protein (PDB: 5iZ7) was aligned to that of rubella virus glycoprotein E1 (PDB: 4ADG). The secondary structure elements were determined using the programs Vector NTI Advance®, DSSP, and ...

show abstract

Functional and evolutionary insight from the crystal structure of rubella virus protein E1

Cited by 94 publications

References 35 publications

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Structural basis of potent Zika–dengue virus antibody cross-neutralization

Rubella virus capsid protein structure and its role in virus assembly and infection

Características de la estructura molecular de las proteínas E del virus Zika y E1 del virus de la rubeola. Posibles implicaciones en el neurotropismo y en las alteraciones del sistema nervioso

Contact Info

Product

Resources

About