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The Tansmembrane Associations of HIV...

Cole, Gregory.

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The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets./
Author:	Cole, Gregory.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	155 p.
Notes:	Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Contained By:	Dissertations Abstracts International81-02B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10980183
ISBN:	9781085588102

The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets.
Cole, Gregory.

The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 155 p.

Source: Dissertations Abstracts International, Volume: 81-02, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2019.

This item is not available from ProQuest Dissertations & Theses.

Many viruses evade the innate immune response through the expression of accessory proteins that modulate the activity of immune system proteins. The HIV-1 protein Vpu functions to downregulate a number of host cell surface proteins within infected cells. For several target proteins, including the NTB-A and PVR receptors and the restriction factor tetherin, downregulation occurs through direct interaction of the proteins' transmembrane (TM) domains. The mechanism through which a single TM domain can interact with a wide range of targets that share no obvious interaction motifs is poorly understood. In this thesis we characterize the TM domain homo and heterooligomerization of Vpu and its human targets, tetherin, NTB-A and PVR. By using a series of fluorophore labeled TM domain peptides we used Forster resonance energy transfer (FRET) to characterize the interactions of Vpu with itself as well as its human targets. Our data show target TM domains compete for interaction with Vpu, suggesting that all targets bind the same helical face, also that formation of each heterooligomer has a similar free energy of association to the Vpu homooligomer. This leads to a model in which Vpu monomers, Vpu homooligomers and Vpu-target heterooligomers coexist and suggests that the binding surface of the Vpu TM domain has been selected for weak binding to multiple targets. We also document the role of the lipid bilayer, specifically lipid phase and hydrophobic thickness, on TM domain assembly within the Vpu-target system. We show that thicker membranes and gel phase lipids non-specifically promote associations of Vpu and its targets without affecting secondary structure. The properties of the lipid bilayer are an important factor in Vpu-target oligomerization and may explain differences in Vpu-target oligomerization in different subcellular compartments. This work provides new insight into the molecular mechanism of Vpu and furthers our knowledge of membrane protein assembly.

ISBN: 9781085588102Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

FRET

The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets.
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245 1 4 $a The Tansmembrane Associations of HIV-1 Vpu and Its Human Targets.
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300 $a 155 p.
500 $a Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
500 $a Advisor: Sharpe, Simon J.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2019.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a Many viruses evade the innate immune response through the expression of accessory proteins that modulate the activity of immune system proteins. The HIV-1 protein Vpu functions to downregulate a number of host cell surface proteins within infected cells. For several target proteins, including the NTB-A and PVR receptors and the restriction factor tetherin, downregulation occurs through direct interaction of the proteins' transmembrane (TM) domains. The mechanism through which a single TM domain can interact with a wide range of targets that share no obvious interaction motifs is poorly understood. In this thesis we characterize the TM domain homo and heterooligomerization of Vpu and its human targets, tetherin, NTB-A and PVR. By using a series of fluorophore labeled TM domain peptides we used Forster resonance energy transfer (FRET) to characterize the interactions of Vpu with itself as well as its human targets. Our data show target TM domains compete for interaction with Vpu, suggesting that all targets bind the same helical face, also that formation of each heterooligomer has a similar free energy of association to the Vpu homooligomer. This leads to a model in which Vpu monomers, Vpu homooligomers and Vpu-target heterooligomers coexist and suggests that the binding surface of the Vpu TM domain has been selected for weak binding to multiple targets. We also document the role of the lipid bilayer, specifically lipid phase and hydrophobic thickness, on TM domain assembly within the Vpu-target system. We show that thicker membranes and gel phase lipids non-specifically promote associations of Vpu and its targets without affecting secondary structure. The properties of the lipid bilayer are an important factor in Vpu-target oligomerization and may explain differences in Vpu-target oligomerization in different subcellular compartments. This work provides new insight into the molecular mechanism of Vpu and furthers our knowledge of membrane protein assembly.
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