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Isolation and analysis of small tran...

Marlatt, Sara Alyssa.

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Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5./
Author:	Marlatt, Sara Alyssa.
Description:	319 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
Contained By:	Dissertation Abstracts International74-11B(E).
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3572042
ISBN:	9781303299568

Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5.
Marlatt, Sara Alyssa.

Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5. - 319 p.

Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.

Thesis (Ph.D.)--Yale University, 2013.

Transmembrane proteins are a unique set of proteins that span the lipid bilayers of cells and mediate diverse cellular processes including ion transport, oxidative phosphorylation, and cell signaling. The membrane-spanning sequences of these proteins play a critical role in the folding and function of their cognate protein, and mutations in these regions can result in a variety of disease phenotypes. Approximately one-third of the genes in the human genome encode transmembrane proteins, but due to their localization in the hydrophobic membrane environment, it is challenging to interrogate the structure and function of the transmembrane segments of these important proteins.

ISBN: 9781303299568Subjects--Topical Terms:

1017719
Biology, Molecular.

Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5.
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100 1 $a Marlatt, Sara Alyssa. $3 2101671
245 1 0 $a Isolation and analysis of small transmembrane protein aptamers that target the HIV coreceptor CCR5.
300 $a 319 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-11(E), Section: B.
500 $a Adviser: Daniel DiMaio.
502 $a Thesis (Ph.D.)--Yale University, 2013.
520 $a Transmembrane proteins are a unique set of proteins that span the lipid bilayers of cells and mediate diverse cellular processes including ion transport, oxidative phosphorylation, and cell signaling. The membrane-spanning sequences of these proteins play a critical role in the folding and function of their cognate protein, and mutations in these regions can result in a variety of disease phenotypes. Approximately one-third of the genes in the human genome encode transmembrane proteins, but due to their localization in the hydrophobic membrane environment, it is challenging to interrogate the structure and function of the transmembrane segments of these important proteins.
520 $a Previous work in the DiMaio lab demonstrated the utility of screening randomized transmembrane protein expression libraries for novel modulators of cellular transmembrane targets. From these libraries we have isolated activators of two distinct single-pass transmembrane proteins, the platelet-derived growth factor beta receptor and the human erythropoietin receptor. In this work, we describe the first application of this approach to construct artificial transmembrane protein aptamers, traptamers, which can inhibit a cellular, multi-pass transmembrane protein target, CCR5. The CC-chemokine receptor 5 (CCR5), is a G protein-coupled receptor with seven transmembrane domains. CCR5 is expressed on monocytes, macrophages, dendritic cells, and T cells, where it functions to mediate leukocyte chemotaxis. Due to functional redundancy among chemokine receptors, CCR5 is not required for normal cell function. However, it is essential as a coreceptor for infection by most sexually-transmitted strains of the human immunodeficiency virus (HIV).
520 $a In order to find new ways to modulate CCR5 and investigate the role of its membrane-spanning regions, we screened a library of small proteins with randomized transmembrane domains and identified six unique traptamer proteins that can specifically reduce cell surface expression of CCR5. These traptamers are active in human T cell lines and block single-cycle pseudotyped HIV reporter viruses and multi-cycle infectious HIV in vitro. All of the traptamers function post-transcriptionally and reduce total protein levels of CCR5. Furthermore, biochemical and genetic evidence strongly suggest that the traptamers interact directly with the transmembrane domains of CCR5 to mediate their effect. Based on the activity of the traptamers in various assays, we have identified three major classes of traptamer proteins. Most of the traptamers show a strong requirement for a single lysine residue in the fifth transmembrane domain of CCR5 in order to downregulate CCR5, but this residue is not required for the traptamers to bind to CCR5. This class of proteins seems to function by targeting CCR5 for degradation in the lysosomal compartment. One traptamer, BY1 shares these characteristics but also seems to mediate crosstalk between CCR5 and CXCR4. The third set of traptamers are distinct from the other two classes based on their ability to reduce both cell surface and intracellular pools of CCR5, independent of proteasome or lysosomal function. These traptamers also rely on a more amino-terminal domain of CCR5 for optimal activity and we hypothesize that they may inhibit translation of CCR5.
520 $a Elucidating the mechanism of action for these different classes of traptamers is important and will likely provide insight into the role of CCR5 transmembrane sequences in its structure, function, and metabolism. In addition, these traptamers may help to inform the design of new anti-HIV approaches. Finally, this work suggests that similar methods could be applied to other multi-pass transmembrane protein targets, providing a helpful tool in understanding the rules that govern transmembrane protein synthesis, trafficking, regulation, and activity.
590 $a School code: 0265.
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Biology, Virology. $3 1019068
690 $a 0307
690 $a 0720
710 2 $a Yale University. $b Genetics. $3 2101672
773 0 $t Dissertation Abstracts International $g 74-11B(E).
790 $a 0265
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3572042