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SAMHD1, a HIV Restriction Factor and...

Tang, Chenxiang.

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SAMHD1, a HIV Restriction Factor and Functions Beyond.

Record Type:	Electronic resources : Monograph/item
Title/Author:	SAMHD1, a HIV Restriction Factor and Functions Beyond./
Author:	Tang, Chenxiang.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2016,
Description:	146 p.
Notes:	Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.
Contained By:	Dissertation Abstracts International78-01B(E).
Subject:	Biophysics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10158178
ISBN:	9781369131864

SAMHD1, a HIV Restriction Factor and Functions Beyond.
Tang, Chenxiang.

SAMHD1, a HIV Restriction Factor and Functions Beyond. - Ann Arbor : ProQuest Dissertations & Theses, 2016 - 146 p.

Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.

Thesis (Ph.D.)--Yale University, 2016.

SAM domain and HD domain-containing protein 1 (SAMHD1) inhibits infection by HIV-1 and other viruses in non-dividing human immune cells. Mutations in SAMHD1 are also implicated in the pathogenesis of chronic lymphocytic leukemia and the autoimmune condition Aicardi-Goutieres syndrome. The antiviral activity of SAMHD1 is negatively modulated by phosphorylation at residue T592. SAMHD1 is a multifunctional enzyme with dNTPase and controversial nuclease activities. The dNTPase activity of SAMHD1 is controlled by the combined action of GTP and all four types of dNTPs with an intriguing mechanism. The contribution of the dNTPase activity and the potential nuclease activity to HIV-1 restriction remains unresolved. My dissertation research focused on answering these key questions about SAMHD1.

ISBN: 9781369131864Subjects--Topical Terms:

518360
Biophysics.

SAMHD1, a HIV Restriction Factor and Functions Beyond.
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300 $a 146 p.
500 $a Source: Dissertation Abstracts International, Volume: 78-01(E), Section: B.
500 $a Adviser: Yong Xiong.
502 $a Thesis (Ph.D.)--Yale University, 2016.
520 $a SAM domain and HD domain-containing protein 1 (SAMHD1) inhibits infection by HIV-1 and other viruses in non-dividing human immune cells. Mutations in SAMHD1 are also implicated in the pathogenesis of chronic lymphocytic leukemia and the autoimmune condition Aicardi-Goutieres syndrome. The antiviral activity of SAMHD1 is negatively modulated by phosphorylation at residue T592. SAMHD1 is a multifunctional enzyme with dNTPase and controversial nuclease activities. The dNTPase activity of SAMHD1 is controlled by the combined action of GTP and all four types of dNTPs with an intriguing mechanism. The contribution of the dNTPase activity and the potential nuclease activity to HIV-1 restriction remains unresolved. My dissertation research focused on answering these key questions about SAMHD1.
520 $a In Chapter 2, I present extensive biochemical and structural data that reveal an exquisite activation mechanism of SAMHD1 via combined action of both GTP and dNTPs. We have obtained twenty-six crystal structures of SAMHD1 in complex with different combinations of GTP and dNTP mixtures, which depict the full spectrum of GTP/dNTP binding at the eight allosteric and four catalytic sites of the SAMHD1 tetramer. Our data demonstrated how SAMHD1 is activated by binding of GTP or dGTP at allosteric site 1 and a dNTP of any type at allosteric site 2. My enzymatic assays further revealed a robust regulatory mechanism of SAMHD1 activity, which bears resemblance to that of the ribonucleotide reductase (RNR) responsible for cellular dNTP production.
520 $a In Chapter 3, I demonstrate that the phosphomimetic mutation T592E reduces the stability of the catalytically active SAMHD1 tetramer and the dNTPase activity of SAMHD1. To better understand the underlying mechanisms, I determined the crystal structures of SAMHD1 variants T592E and T592V. While the neutral substitution T592V does not perturb the structure, the charged T592E induces large conformational changes, likely triggered by electrostatic repulsion from a distinct negatively charged environment surrounding T592. The phosphomimetic mutation resulted in a significant decrease in the population of active SAMHD1 tetramers and hence the dNTPase activity is substantially decreased. In.
520 $a Chapter 4, I show that the controversial nuclease activity of SAMHD1 is likely associated with the contaminating proteins during purification, and not responsible for HIV restriction. With rigorous purification, the apparent weak nuclease activity decreased to an insignificant degree. The residual nuclease activity could not be assigned to any potential catalytic site, including that for the dNTPase activity. I further demonstrated that a number of HIV-1 restriction-defective SAMHD1 variants are dNTPase-deficient but maintain the same level of residual nuclease activity as the WT enzyme, indicating that the putative RNase activity of SAMHD1 is not responsible for viral restriction. These results establish a comprehensive framework for a mechanistic understanding of the important functions of SAMHD1 in the regulation of cellular dNTP levels, as well as in HIV restriction and the pathogenesis of CLL and AGS.
590 $a School code: 0265.
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