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Insight into Interactions of APOBEC3...

Ziegler, Samantha Josephine.

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Insight into Interactions of APOBEC3 Proteins with DNA and HIV Vif.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Insight into Interactions of APOBEC3 Proteins with DNA and HIV Vif./
作者:	Ziegler, Samantha Josephine.
出版者:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:	133 p.
附註:	Source: Dissertations Abstracts International, Volume: 81-02, Section: B.
Contained By:	Dissertations Abstracts International81-02B.
標題:	Biochemistry. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13806893
ISBN:	9781085758086

Insight into Interactions of APOBEC3 Proteins with DNA and HIV Vif.
Ziegler, Samantha Josephine.

Insight into Interactions of APOBEC3 Proteins with DNA and HIV Vif. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 133 p.

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

Thesis (Ph.D.)--Yale University, 2019.

This item must not be sold to any third party vendors.

The cellular innate immune response is the first reaction to any infection. Our lab aims to understand the molecular mechanisms of the innate immune response because it is vital for effective treatment and drug design. My dissertation research is focused on the APOBEC3, or A3, family of proteins, which is a potent defense mechanism that is activated in response to a variety of viral infections. A3 proteins recognize specific nucleotide sequences, called hotspots, on ssDNA and deaminate deoxycytidine to deoxyuridine, introducing mutations in foreign DNA. A3 proteins hypermutate the viral genome, causing severe genomic defects that often decrease or eliminate viral infectivity. Some A3 proteins, such as A3A, A3B, and A3H, localize to the nucleus where they lack the ability to distinguish between foreign and host ssDNA. Therefore, expression of A3 proteins has been correlated with certain types of cancer based on the mutational pattern observed. Understanding how A3 proteins interact with their DNA substrates may provide information on how to distinguish between beneficial A3 activity versus that which is detrimental to the host.To determine how A3 proteins interact with substrate DNA at a molecular level, our lab crystallized A3G bound to a substrate nucleotide of ssDNA. From these results, I concluded that A3 proteins have multiple mechanisms for selecting a target substrate. The primary mechanism of substrate selection is through loop 7 of any A3 protein. I defined a secondary mechanism where loop 1 of A3G impacts the preference for specific nucleotides in the hotspot. Next, to probe the secondary selection mechanism in the rest of the A3 proteins, I used biochemistry to determine that the activity of A3A can be affected by a single amino acid in loop 1. These experiments also confirmed that the secondary mode of substrate selectivity is affected by three residues in loop 1 of the A3 protein. These results are useful not only in understanding the potential of cancer progression and the mechanics of the host defense system against viruses, but also provide more nuanced details for advancing gene editing technologies.In addition to studying the interaction between APOBEC3 proteins and their substrate DNA, we also explored how viruses have evolved their own protective mechanisms against host A3 proteins. Understanding the arms race between viral components and host A3 proteins is necessary for further development of treatments for viral infections. Particularly, I am interested in understanding the interaction between the HIV accessory protein Vif and the APOBEC3 proteins. I developed a novel full-length A3G chimera construct that behaves in solution and interacts with the Vif-E3 ligase. Using cryo-electron microscopy (cryo-EM), I have begun to structurally characterize the interaction between Vif, the cellular E3 ligase machinery, and A3G.Ultimately, learning about the A3 family of proteins involved in the innate immune response has led to many interesting research questions about how the body defends itself against viral infections, but also how those mechanisms can backfire and cause damage to our own genome. We have biochemically and structurally characterized multiple A3 proteins that have furthered our understanding of the molecular mechanisms that underlie host innate immunity.

ISBN: 9781085758086Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Apobec3

Insight into Interactions of APOBEC3 Proteins with DNA and HIV Vif.
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520 $a The cellular innate immune response is the first reaction to any infection. Our lab aims to understand the molecular mechanisms of the innate immune response because it is vital for effective treatment and drug design. My dissertation research is focused on the APOBEC3, or A3, family of proteins, which is a potent defense mechanism that is activated in response to a variety of viral infections. A3 proteins recognize specific nucleotide sequences, called hotspots, on ssDNA and deaminate deoxycytidine to deoxyuridine, introducing mutations in foreign DNA. A3 proteins hypermutate the viral genome, causing severe genomic defects that often decrease or eliminate viral infectivity. Some A3 proteins, such as A3A, A3B, and A3H, localize to the nucleus where they lack the ability to distinguish between foreign and host ssDNA. Therefore, expression of A3 proteins has been correlated with certain types of cancer based on the mutational pattern observed. Understanding how A3 proteins interact with their DNA substrates may provide information on how to distinguish between beneficial A3 activity versus that which is detrimental to the host.To determine how A3 proteins interact with substrate DNA at a molecular level, our lab crystallized A3G bound to a substrate nucleotide of ssDNA. From these results, I concluded that A3 proteins have multiple mechanisms for selecting a target substrate. The primary mechanism of substrate selection is through loop 7 of any A3 protein. I defined a secondary mechanism where loop 1 of A3G impacts the preference for specific nucleotides in the hotspot. Next, to probe the secondary selection mechanism in the rest of the A3 proteins, I used biochemistry to determine that the activity of A3A can be affected by a single amino acid in loop 1. These experiments also confirmed that the secondary mode of substrate selectivity is affected by three residues in loop 1 of the A3 protein. These results are useful not only in understanding the potential of cancer progression and the mechanics of the host defense system against viruses, but also provide more nuanced details for advancing gene editing technologies.In addition to studying the interaction between APOBEC3 proteins and their substrate DNA, we also explored how viruses have evolved their own protective mechanisms against host A3 proteins. Understanding the arms race between viral components and host A3 proteins is necessary for further development of treatments for viral infections. Particularly, I am interested in understanding the interaction between the HIV accessory protein Vif and the APOBEC3 proteins. I developed a novel full-length A3G chimera construct that behaves in solution and interacts with the Vif-E3 ligase. Using cryo-electron microscopy (cryo-EM), I have begun to structurally characterize the interaction between Vif, the cellular E3 ligase machinery, and A3G.Ultimately, learning about the A3 family of proteins involved in the innate immune response has led to many interesting research questions about how the body defends itself against viral infections, but also how those mechanisms can backfire and cause damage to our own genome. We have biochemically and structurally characterized multiple A3 proteins that have furthered our understanding of the molecular mechanisms that underlie host innate immunity.
590 $a School code: 0265.
650 4 $a Biochemistry. $3 518028
650 4 $a Biophysics. $3 518360
650 4 $a Molecular biology. $3 517296
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653 $a Host-viral interactions
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653 $a Structural biology
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