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THE CRYSTAL STRUCTURE OF APOBEC-2
AND IMPLICATIONS FOR APOBEC ENZYMES
by
Courtney Prochnow
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR BIOLOGY)
May 2008
Copyright 2008 Courtney Prochnow
Object Description
| Title | The crystal structure of APOBEC-2 and implications for APOBEC enzymes |
| Author | Prochnow, Courtney |
| Author email | cprochno@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Biology |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2008-01-25 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-02-21 |
| Advisor (committee chair) | Chen, Xiaojiang |
| Advisor (committee member) |
Goodman, Myron Chen, Lin Bau, Robert |
| Abstract | APOBEC-2 (Apo2) belongs to the Apolioprotein B (APOB) mRNA-editing enzyme catalytic polypeptide (APOBEC) family of cytidine deaminases that modify genes by deaminating cytosines in mRNA coding sequences and cytidines in ssDNA (Franca et al., 2006). APOBEC deaminases have remarkably diverse functions comprising antibody maturation, inactivation of viral genomes including Human Immunodeficiency virus-1 (HIV-1) and Hepatitis B virus (HBV), inhibition of retrotransposition, and RNA editing. The repertoire of APOBECs and their respective activities are continuously expanding to include new functions and sub-classes of the family.; The APOBEC family is composed of APOBEC-1 (Apo1), Apo2, AID, and APOBEC-3 (3A, 3B, 3C, 3DE, 3F, 3G, and3H) and APOBEC-4 (Conticello et al., 2004; Sawyer et al., 2004). Previous comparative modeling of APOBECs has been performed using the structures of free nucleotide cytidine deaminases (fntCDA) which deaminate free cytidine/cytosine bases which share considerable sequence homology with APOBECs. However, a comprehension of the molecular mechanisms of the APOBEC enzymes has been limited by the lack of 3-dimensional structures of APOBEC proteins that deaminate large nucleic acid substrates.; Here, a body of work is presented that describes the 2.5Å crystal structure of Apo2, which is the first X-ray analysis reported for an APOBEC enzyme. The Apo2 structure reveals an elongated tetramer that differs markedly from the square-shaped tetramer of fntCDAs. In Apo2, two long a-helices of a monomer structure prevent the formation of a square-shaped tetramer and facilitate formation of the rod-shaped tetramer via head-to-head interactions of two APO2 dimers. The Apo2 active sites can accommodate large RNA/DNA substrates and the structure reveals a possible "built in" mechanism for regulating substrate access and enzyme activity.; Extensive sequence homology among APOBEC family members allows us to test Apo2 structure-based predictions using activation-induced cytidine deaminase (AID). Furthermore, the Apo2 structure can be used as a template for comparative modeling to gain both structural and functional insight into these important enzymes. |
| Keyword | APOBEC; cytidine deaminase; HIV; cytidine deamination; activation induced cytidine deaminase; AID; APOBEC-2 |
| 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 |
| Type | texts |
| Legacy record ID | usctheses-m1025 |
| Rights | Prochnow, Courtney |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Prochnow-20080221 |
| Archival file | uscthesesreloadpub_Volume44/etd-Prochnow-20080221.pdf |
Description
| Title | Page 1 |
| Full text | THE CRYSTAL STRUCTURE OF APOBEC-2 AND IMPLICATIONS FOR APOBEC ENZYMES by Courtney Prochnow A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR BIOLOGY) May 2008 Copyright 2008 Courtney Prochnow |
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