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The Characterization of Glycoprotein Interactions and Triggering Mechanisms in Herpes Simplex Virus 1 Membrane Fusion.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	The Characterization of Glycoprotein Interactions and Triggering Mechanisms in Herpes Simplex Virus 1 Membrane Fusion./
Author:	Pataki, Zemplen.
Description:	1 online resource (171 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 84-03, Section: B.
Contained By:	Dissertations Abstracts International84-03B.
Subject:	Virology. -
Online resource:	click for full text (PQDT)
ISBN:	9798351450193

The Characterization of Glycoprotein Interactions and Triggering Mechanisms in Herpes Simplex Virus 1 Membrane Fusion.
Pataki, Zemplen.

The Characterization of Glycoprotein Interactions and Triggering Mechanisms in Herpes Simplex Virus 1 Membrane Fusion. - 1 online resource (171 pages)

Source: Dissertations Abstracts International, Volume: 84-03, Section: B.

Thesis (Ph.D.)--Tufts University-Graduate School of Biomedical Sciences, 2024.

Includes bibliographical references

Herpes simplex virus 1 (HSV-1) infects the majority of the world's population for life and causes cold sores and encephalitis. HSV-1 infects cells by fusing its membrane envelope with a cellular membrane, using viral glycoproteins gD, gH, gL, and gB. gD binds to a receptor on the target cell and activates the gH/gL heterodimer. gH/gL activates gB to refold from a prefusion to a postfusion conformation to catalyze membrane fusion. However, it is unknown how these glycoproteins interact with each other before and during this process, and the molecular mechanisms by which they activate each other. Using a split-luciferase interaction assay, we found that pairs of the viral glycoproteins interact with each other in a stable manner through several domains prior to and during fusion. Interestingly, the transmembrane and cytoplasmic domains (CTD) of the glycoproteins were particularly important for the interactions. The cytoplasmic domains of gH and gB are also known to play important roles in fusion, but how gH activates gB is unknown. We identified two new regulatory elements in the gH cytotail (gHCT) and gBCTD: residue V831 in the gHCT and a surface pocket between adjacent protomers of the gBCTD. Based on mutagenesis and structural modeling, we propose that gH V831 serves as a "wedge" that binds in the pocket of the gBCTD "clamp" to activate gB for membrane fusion. Overall, we propose a "conformational cascade" model of the HSV-1 membrane fusion pathway. The glycoproteins assemble into a gD-gH/gL-gB complex prior to fusion, with gH/gL positioned between gD and gB. Once gD binds to a receptor, the preassembled complex allows for efficient transduction of the activating signal from gD to gH/gL to gB by conformational changes. The conformational change of gH/gL causes the V831 gHCT wedge to insert into the gBCTD pocket. This pushes the gBCTD protomers apart, releasing the inhibitory gBCTD clamp and allowing gB to refold and cause fusion.The interactions elucidated in this work could provide novel therapeutic targets to disrupt HSV-1 membrane fusion and viral infection. Similar glycoprotein interactions and mechanisms could be at play in other herpesviruses and multicomponent viral membrane fusion systems.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798351450193Subjects--Topical Terms:

644995
Virology.
Subjects--Index Terms:

FusionIndex Terms--Genre/Form:

554714
Electronic books.

The Characterization of Glycoprotein Interactions and Triggering Mechanisms in Herpes Simplex Virus 1 Membrane Fusion.
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504 $a Includes bibliographical references
520 $a Herpes simplex virus 1 (HSV-1) infects the majority of the world's population for life and causes cold sores and encephalitis. HSV-1 infects cells by fusing its membrane envelope with a cellular membrane, using viral glycoproteins gD, gH, gL, and gB. gD binds to a receptor on the target cell and activates the gH/gL heterodimer. gH/gL activates gB to refold from a prefusion to a postfusion conformation to catalyze membrane fusion. However, it is unknown how these glycoproteins interact with each other before and during this process, and the molecular mechanisms by which they activate each other. Using a split-luciferase interaction assay, we found that pairs of the viral glycoproteins interact with each other in a stable manner through several domains prior to and during fusion. Interestingly, the transmembrane and cytoplasmic domains (CTD) of the glycoproteins were particularly important for the interactions. The cytoplasmic domains of gH and gB are also known to play important roles in fusion, but how gH activates gB is unknown. We identified two new regulatory elements in the gH cytotail (gHCT) and gBCTD: residue V831 in the gHCT and a surface pocket between adjacent protomers of the gBCTD. Based on mutagenesis and structural modeling, we propose that gH V831 serves as a "wedge" that binds in the pocket of the gBCTD "clamp" to activate gB for membrane fusion. Overall, we propose a "conformational cascade" model of the HSV-1 membrane fusion pathway. The glycoproteins assemble into a gD-gH/gL-gB complex prior to fusion, with gH/gL positioned between gD and gB. Once gD binds to a receptor, the preassembled complex allows for efficient transduction of the activating signal from gD to gH/gL to gB by conformational changes. The conformational change of gH/gL causes the V831 gHCT wedge to insert into the gBCTD pocket. This pushes the gBCTD protomers apart, releasing the inhibitory gBCTD clamp and allowing gB to refold and cause fusion.The interactions elucidated in this work could provide novel therapeutic targets to disrupt HSV-1 membrane fusion and viral infection. Similar glycoprotein interactions and mechanisms could be at play in other herpesviruses and multicomponent viral membrane fusion systems.
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653 $a Glycoprotein
653 $a Herpes
653 $a Interaction
653 $a Luciferase
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