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A STRUCTURE BASED STUDY OF THE HIV RESTRICTION FACTOR
APOBEC3G
by
Lauren Georgianna Holden
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Ful llment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
May 2011
Copyright 2011 Lauren Georgianna Holden
Object Description
| Title | A structure based study of the HIV restriction factor APOBEC3G |
| Author | Holden, Lauren Georgianna |
| Author email | lholden@usc.edu; ciaobella8682@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Biology |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2011-01-28 |
| Date submitted | 2011 |
| Restricted until | Unrestricted |
| Date published | 2011-03-01 |
| Advisor (committee chair) | Chen, Xiaojiang S. |
| Advisor (committee member) |
Chen, Lin Goodman, Myron F. Warshel, Arieh |
| Abstract | The Apolipoprotein B editing enzyme catalytic polypeptide-like (APOBEC) family of 11 proteins deaminate cytidines on either single-stranded DNA (ssDNA) or RNA substrates, introducing C to U mutations [28]. These mutagenic proteins are vital for a variety of biological purposes, ranging from proper metabolism to development of strict and efficient antibodies to prevention of virus infection [28]. This activity is controlled by a signature domain motif His-Xaa-Glu-Xaa₂₃₋₂₈-Pro-Cys-Xaa₂₋₄-Cys, where the histidine and two cysteine residues coordinate the Zinc (Zn) required for catalysis [24, 28, 50]. A duplication event occurred during evolution that produced four APOBECs with two of these domains [29, 54]. One such member is APOBEC3G (A3G). In A3G, it has been shown that only the second domain (CD2) is catalytically active, while the other is responsible for RNA binding and various protein interactions [24].; A3G has been shown to potently restrict human immunodeficiency virus (HIV) replication [24, 50]. A3G introduces multiple dC to dU deaminations in the viral cDNA during reverse transcription, triggering degradation of the viral cDNA or resulting in defective proviruses [24, 50]. A3G also appears to interfere with successful infection by HIV in a non-deamination dependent manner [24, 50]. To counteract this antiviral activity of A3G, HIV-1 encodes the Vif protein that binds and targets A3G for proteosome- mediated degradation [24]. However, in the absence of Vif, A3G can effectively restrict HIV-1 replication.; Prior to this study, structural information for this family of proteins consisted of the APOBEC2 (A2) protein, which has an undetermined physiological function [98]. Here, this study presents the first X-ray structure of the C-terminal catalytic domain (A3G-CD2) [49]. The A3G-CD2 structure highlights key functional regions, allowing for insights to be made into substrate binding and specificity. Further studies of A3G were performed to answer questions of substrate recognition, oligomerization, and over-all double domain structure. Altogether, the information presented here advanced the understanding of A3G’s enzymatic activity and provides a solid base for future insightful drug design aimed at improving A3G’s intrinsic HIV restriction. |
| Keyword | cytidine deaminase; X-ray crystallography; anti-HIV |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3673 |
| Contributing entity | University of Southern California |
| Rights | Holden, Lauren Georgianna |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | cisadmin@dots.usc.edu |
| Filename | etd-Holden-4343 |
| Archival file | uscthesesreloadpub_Volume23/etd-Holden-4343.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Repository email | cisadmin@dots.usc.edu |
| Full text | A STRUCTURE BASED STUDY OF THE HIV RESTRICTION FACTOR APOBEC3G by Lauren Georgianna Holden A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Ful llment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR BIOLOGY) May 2011 Copyright 2011 Lauren Georgianna Holden |
