Crystal Structure of Glycoprotein B from Herpes Simplex Virus 1

Heldwein, Ekaterina E.; Lou, Huan; Bender, Florent C.; Cohen, Gary H.; Eisenberg, Roselyn J.; Harrison, Stephen C.

doi:10.1126/science.1126548

Cited by 507 publications

(832 citation statements)

References 30 publications

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“…Mutations in the cytoplasmic tail of gB enhance cell-cell fusion of HSV-1 isolates (38-40) and also enhance cell-cell fusion of HSV glycoproteins in plasmid-based fusion assays (20,41,42) in a manner similar to that seen for mutations in the cytoplasmic tail of the fusion protein of HIV, gp120/gp41 (43). Furthermore, the recently solved crystal structure of HSV-1 gB lacking the transmembrane domain and cytoplasmic tail revealed a striking homology to the structure of vesicular stomatitis virus G fusion protein (15). Both gp120/gp41 and G proteins are active during Phase III of fusion.…”

Section: Discussionmentioning

confidence: 99%

“…However, their exact role in the fusion mechanism has yet to be elucidated. There are two models for fusion: the regulatory/structural model, where one glycoprotein serves as a regulator or a support for the fusogenic activity of the other (14,15); and the sequential model, where each glycoprotein functions at a different stage in the fusion process (7). If the sequential model is correct, it may be possible to separate the function of the glycoproteins in fusion through assays that detect a fusion intermediate, such as hemifusion.…”

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confidence: 99%

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Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

Subramanian

Geraghty

2007

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

158

145

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Virus-induced membrane fusion can be subdivided into three phases defined by studies of class I and class II fusion proteins. During Phase I, two membranes are brought into close apposition. Phase II marks the mixing of the outer membrane leaflets leading to formation of a hemifusion intermediate. A fusion pore stably forms and expands in Phase III, thereby completing the fusion process. Herpes simplex virus type 1 (HSV-1) requires four glycoproteins to complete membrane fusion, but none has been defined as class I or II. Therefore, we investigated whether HSV-1-induced membrane fusion occurred following the same general phases as those described for class I and II proteins. In this study we demonstrate that glycoprotein D (gD) and the glycoprotein H and glycoprotein L complex (gHL) mediated lipid mixing indicative of hemifusion. However, content mixing and full fusion required glycoprotein B (gB) to be present along with gD and gHL. Our results indicate that, like class I and II fusion proteins, fusion mediated by HSV-1 glycoproteins occurred through a hemifusion intermediate. In addition, both gB and gHL are probably directly involved in the fusion process. From this, we propose a sequential model for fusion via HSV-1 glycoproteins whereby gD is required for Phase I, gHL is required for Phase II, and gB is required for Phase III. We further propose that glycoprotein H and gB are likely to function sequentially to promote membrane fusion in other herpesviruses such as Epstein-Barr virus and human herpesvirus 8.lipid transfer ͉ membrane fusion ͉ fluorescence microscopy S tudies using class I and class II fusion proteins have demonstrated that virus-induced membrane fusion can be subdivided into three phases (1, 2). Phase I involves bringing opposing membranes into close proximity through a viral glycoprotein binding a cellular receptor. Phase II involves the initiation of lipid mixing between the two apposed membranes and is completed when the outer membrane leaflets are mixed to form an intermediate called hemifusion. Phase III begins when the inner membrane leaflets are mixed and continues the pore formation and expansion. The completion of Phase III signifies the completion of the fusion process. The three phases of membrane fusion (close apposition, hemifusion, and complete fusion) are useful to characterize functions of viral glycoproteins in the fusion process (1, 3, 4). Fusion proteins that have Phase I function bring membranes in close apposition and ultimately result in the initiation of the fusion process. Fusion proteins that have Phase II function are capable of mixing outer membrane leaflets leading to hemifusion. Phase III fusion proteins are capable of forming and expanding a fusion pore. For many viruses, one or two fusion proteins can carry out all phases of membrane fusion. The fusion process has yet to be characterized for viruses that require more than two fusion glycoproteins, and a major issue is whether multiple glycoproteins mediate fusion through a hemifusion intermediate.Herpes simplex ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

Subramanian

Geraghty

2007

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

158

145

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“…The structure of herpes simplex virus 1 (HSV1, a double-stranded DNA virus) glycoprotein gB [57] was published at the same time as that of G th post-fusion state. Comparison of the two structures revealed that their folds are the same and that they have a common evolutionary origin that could not be detected by looking at the amino acid sequences (Fig.…”

Section: An Unexpected Homologymentioning

confidence: 99%

Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited

Roche

Albertini

Lepault

et al. 2008

Cell. Mol. Life Sci.

127

138

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Abstract. Glycoprotein G of the vesicular stomatitis virus (VSV) is involved in receptor recognition at the host cell surface and then, after endocytosis of the virion, triggers membrane fusion via a low pHinduced structural rearrangement. G is an atypical fusion protein, as there is a pH-dependent equilibrium between its pre-and post-fusion conformations. The atomic structures of these two conformations reveal that it is homologous to glycoprotein gB of herpesviruses and that it combines features of the previously characterized class I and class II fusion proteins.Comparison of the structures of G pre-and postfusion states shows a dramatic reorganization of the molecule that is reminiscent of that of paramyxovirus fusion protein F. It also allows identification of conserved key residues that constitute pH-sensitive molecular switches. Besides the similarities with other viral fusion machineries, the fusion properties and structures of G also reveal some striking particularities that invite us to reconsider a few dogmas concerning fusion proteins.

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“…(1) the PMI of extended conformation internal fusion peptides postulated from structures of dengue, Semliki forest, herpes, and vesicular stomatitis viral fusion proteins; (2) the PMI of helical influenza fusion peptide determined from electron spin resonance experiments; and (3) a PMI model based on the HFP-F8W fluorescence measurements (37,61,62,(93)(94)(95)(96). However, the locations of lipids in the perturbed leaflet in the PMI model are not clear.…”

Section: Insertion Modelsmentioning

confidence: 99%

Solid-State Nuclear Magnetic Resonance Measurements of HIV Fusion Peptide to Lipid Distances Reveal the Intimate Contact of β Strand Peptide with Membranes and the Proximity of the Ala-14−Gly-16 Region with Lipid Headgroups

2007

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Human immunodeficiency virus (HIV) infection begins with fusion between viral and host cell membranes and is catalyzed by the HIV gp41 fusion protein. The ~20 N-terminal apolar residues of gp41 are called the HIV fusion peptide (HFP), interact with the host cell membrane, and play a key role in fusion. In this study, the membrane location of peptides which contained the HFP sequence AVGIGALFLGFLGAAGSTMGARS was probed in samples containing either only phospholipids or phospholipids and cholesterol. Four HFPs were examined which each contained 13 CO labeling at three sequential residues between G5 and G16. The 13 CO chemical shifts indicated that HFP had predominant β strand conformation over the labeled residues in the samples. The internuclear distances between the HFP 13 COs and the lipid 31 Ps were measured using solid-state nuclear magnetic resonance rotational-echo double resonance experiments. The closest 13 CO-31 P distances of 5-6 Å were observed for HFP labeled between A14 and G16 and correlated with intimate association of β strand HFP and membranes. These results were confirmed with measurements using HFPs singly 13 CO labeled at A6 or A14. To our knowledge, these data are the first measurements of distances between HIV fusion peptide nuclei and lipid P and qualitative models of membrane location of oligomeric β strand HFP are presented which are consistent with the experimental data. Observation of intimate contact between β strand HFP and membranes provides rationale for further investigation of the relationship between structure and fusion activity for this conformation. KeywordsHIV; fusion peptide; membrane; carbonyl; phosphorus; REDOR; NMR The infection of enveloped viruses such as human immunodeficiency virus (HIV) begins with fusion between the viral and host cell membranes (1-4). Fusion may be catalyzed by fusion proteins and several models of fusion protein catalysis have been proposed (2,(5)(6)(7). For HIV, fusion is catalyzed by a "gp160" glycoprotein complex which is incorporated in the virus membrane and is composed of two non-covalently associated subunits "gp120" and "gp41". The gp120 subunit lies outside the virus and binds to receptors in the target cell membrane and the gp41 subunit contains a region inside HIV as well as a single-pass transmembrane domain *To whom correspondence should be addressed. Telephone: 517-355-9715. Fax: 517-353-1793. Email: weliky@chemistry.msu.edu. † This work was supported by NIH award AI47153 to D. P. W. NIH Public Access Author ManuscriptBiochemistry. Author manuscript; available in PMC 2009 January 27. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript (8,9). The ~170-residue ectodomain of gp41 lies outside HIV and is subdivided into a more C-terminal "soluble ectodomain" and a ~20-residue N-terminal fusion peptide (HFP) which is apolar and fairly conserved. The HFP is believed to interact with the target cell membrane after gp120 binds to cellular receptors and fusion is greatly disrupted by mutation or deletion of the H...

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Crystal Structure of Glycoprotein B from Herpes Simplex Virus 1

Cited by 507 publications

References 30 publications

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

Herpes simplex virus type 1 mediates fusion through a hemifusion intermediate by sequential activity of glycoproteins D, H, L, and B

Structures of vesicular stomatitis virus glycoprotein: membrane fusion revisited

Solid-State Nuclear Magnetic Resonance Measurements of HIV Fusion Peptide to Lipid Distances Reveal the Intimate Contact of β Strand Peptide with Membranes and the Proximity of the Ala-14−Gly-16 Region with Lipid Headgroups

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