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Experimental Determination of the Topology of the HIV-1 gp41 C-Terminal Tail

Steckbeck, Jonathan (2012) Experimental Determination of the Topology of the HIV-1 gp41 C-Terminal Tail. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The C-terminal tail (CTT) of HIV gp41 has been traditionally viewed as a cytoplasmic domain. Genetic studies demonstrating functional interactions between the CTT and various intracellular partners have implicitly reinforced this view. However, antibody neutralization data and biochemical studies have suggested that the CTT is, or can be, externally localized under certain condition. Additionally, other studies have demonstrated that the CTT is dispensable for in vitro virus replication. After nearly three decades of HIV research, the function and structure of the CTT remain elusive.

Our goals, then, were twofold: (i) to determine the overall conservation of the CTT in an attempt to provide an understanding of the functional and structural relevance of the CTT; and, (ii) to provide an experimental topological map of the CTT in an attempt to understand and align observed CTT topology(ies) with the functional necessity of a cytoplasmic CTT. We believe that we made significant contributions to the understanding of CTT topology and its relationship to current published functional studies.

The initial studies demonstrated that the CTT sequence is conserved at a level that is intermediate between the highly variable gp120 region and the relatively conserved gp41 ectodomain. Additionally, physicochemical and structural properties of CTT sequences were found to be conserved in spite of the relatively high sequencevariability. These studies demonstrated for the first time that the CTT sequence, while highly variable, contains highly conserved structural and chemical properties that suggest a functional requirement for the CTT.

Topology studies of the CTT indicated that the topology of the CTT can be distinct between the surface of Env-expressing cells and viral particles. Additionally, dynamic rearrangement of the CTT was observed as a function of antibody neutralization. These findings prompted a theoretical study of gp41 CTT predicted topology and the proposal of a topological model that we believe is consistent with all published studies regarding the localization of the CTT.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Steckbeck, Jonathanjds170@pitt.eduJDS170
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMontelaro, Ronald C.rmont@pitt.eduRMONT
Committee MemberCascio,
Committee MemberDay, Billybday@pitt.eduBDAY
Committee MemberKlein-Seetharaman,
Committee MemberSmithgall, Thomastsmithga@pitt.eduTSMITHGA
Date: 8 February 2012
Date Type: Publication
Defense Date: 15 December 2011
Approval Date: 8 February 2012
Submission Date: 17 January 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 215
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biochemistry and Molecular Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Membrane protein topology, HIV, protein biochemistry
Date Deposited: 08 Feb 2012 17:34
Last Modified: 15 Nov 2016 13:55


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