Mapping the Structure and Function of the E1 and E2 Glycoproteins in Alphaviruses

Mukhopadhyay, Suchetana; Zhang, Wei; Gabler, Stefan; Chipman, Paul R.; Strauss, Ellen G.; Strauss, James H.; Baker, Timothy S.; Kühn, Richard; Rossmann, Michael G.

doi:10.1016/j.str.2005.07.025

Cited by 170 publications

(203 citation statements)

References 55 publications

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“…In alphaviruses, the glycoproteins have a cytoplasmic domain that is anchored in the nucleocapsid (9). Similarly, in RV the short predicted transmembrane and/or cytoplasmic domains of the RV E2 glycoprotein may serve as an anchor on the capsid protein (23).…”

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

confidence: 99%

“…1B). Similar to capsid proteins of alphaviruses (9) and small icosahedral RNA plant viruses (10), about 100 amino-terminal residues of RV capsid protein are enriched in basic amino acids. These basic residues are generally associated with the RNA viral genome and are disordered, implying that there is no unique structure for the RNA protein complex.…”

mentioning

confidence: 99%

“…These basic residues are generally associated with the RNA viral genome and are disordered, implying that there is no unique structure for the RNA protein complex. In alphaviruses, the C-terminal part of the capsid proteins forms the structural framework of the nucleocapsids (9,11). The RV capsid protein not only packages the RNA genome but also is involved in viral transcription and replication.…”

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confidence: 99%

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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.

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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 ...

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

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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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.

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“…19 The alphaviruses have highly organized icosahedral protein shells with an associated membrane. [20][21][22] The outer protein shell contains 240 copies of glycoproteins, E1 and E2. 20,23,24 E1 causes cell fusion, whereas E2 is predominantly the protein responsible for cell membrane attachment.…”

Section: Introductionmentioning

confidence: 99%

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Moussavi

et al. 2009

Cancer Gene Ther

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In this study, we took advantage of the overexpression of human epidermal growth factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with modified envelope proteins that bind antibodies to specific cell-surface antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses were able to selectively infect androgen-sensitive LNCaP and castrationresistant C4-2 human prostate cancer cell lines, both of which express high levels of HER-2. To test for a therapeutic effect, we engineered our antibody-binding lentiviruses to express thymidine kinase, which can convert the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2 cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2 xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound lentivirus expressed luciferase, although the latter route was less tumor specific. When a prostate-specific promoter for governing luciferase expression was combined with trastuzumab-mediated delivery, there was a further enrichment in targeting viral gene expression in prostate tumors. In conclusion, we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody.

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“…The virus consists of a central core with diameter of ∼400 Å with the icosahedrally organized capsid proteins surrounding the viral genome. The nucleocapsid core is enveloped by a lipid membrane into which the E1 and E2 glycoproteins are inserted (9). The mature CHIKV particle has a diameter of 700 Å.…”

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confidence: 99%

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

Long

Fong

Austin

et al. 2015

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

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Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes severe acute and chronic disease in humans. Although highly inhibitory murine and human monoclonal antibodies (mAbs) have been generated, the structural basis of their neutralizing activity remains poorly characterized. Here, we determined the cryo-EM structures of chikungunya virus-like particles complexed with antibody fragments (Fab) of two highly protective human mAbs, 4J21 and 5M16, that block virus fusion with host membranes. Both mAbs bind primarily to sites within the A and B domains, as well as to the B domain's β-ribbon connector of the viral glycoprotein E2. The footprints of these antibodies on the viral surface were consistent with results from loss-of-binding studies using an alanine scanning mutagenesis-based epitope mapping approach. The Fab fragments stabilized the position of the B domain relative to the virus, particularly for the complex with 5M16. This finding is consistent with a mechanism of neutralization in which anti-CHIKV mAbs that bridge the A and B domains impede movement of the B domain away from the underlying fusion loop on the E1 glycoprotein and therefore block the requisite pH-dependent fusion of viral and host membranes. chikungunya virus-antibody complexes | cryo-electron microscopy structure | neutralizing mechanism | viral fusion inhibition C hikungunya virus (CHIKV) is an enveloped, positive-stranded RNA virus that belongs to the alphavirus genus of the Togaviridae family (1, 2). CHIKV is transmitted to humans by Aedes species mosquitoes and causes a debilitating febrile illness associated with acute and chronic arthritis (3, 4). Since the first human CHIKV infection was reported in East Africa in 1952 (5), epidemics of CHIKV have occurred in Africa, Asia, and Europe (6, 7). A CHIKV outbreak in the Caribbean area in late 2013 spread through the Americas and caused about 1.4 million infections (8). Despite its global disease burden and risk of spread, there is no available vaccine or effective antiviral drug for CHIKV.The genome of CHIKV is ∼11.8 kb long and encodes nine viral proteins, five of which are structural (capsid, E3, E2, 6K, and E1) (2). These structural proteins are translated as a single polyprotein, which is then cleaved into the capsid, p62, 6K, and E1 proteins by cellular and viral proteases. During maturation, p62 is cleaved to release E3, which protects the fusion loop in the immature virus. The virus consists of a central core with diameter of ∼400 Å with the icosahedrally organized capsid proteins surrounding the viral genome. The nucleocapsid core is enveloped by a lipid membrane into which the E1 and E2 glycoproteins are inserted (9). The mature CHIKV particle has a diameter of 700 Å. The E2 glycoprotein binds to uncharacterized cellular receptors to initiate virus entry into host cells, whereas E1 glycoprotein participates in virus-host cell membrane fusion (10, 11). Although the E3 and 6K proteins contribute to virus assembly and maturation, they are released during the format...

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Mapping the Structure and Function of the E1 and E2 Glycoproteins in Alphaviruses

Cited by 170 publications

References 55 publications

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

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

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Cryo-EM structures elucidate neutralizing mechanisms of anti-chikungunya human monoclonal antibodies with therapeutic activity

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