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Site-Specific Structure and Dynamics of Polyglutamine-Containing Amyloid Fibrils and the Caveolin Scaffolding Domain by Magic Angle Spinning Solid-State NMR

Hoop, Cody (2014) Site-Specific Structure and Dynamics of Polyglutamine-Containing Amyloid Fibrils and the Caveolin Scaffolding Domain by Magic Angle Spinning Solid-State NMR. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Protein assemblies and membrane associations play important roles in health and disease. Structural studies of these biological complexes are thus vital, but are often unfeasible by conventional tools in structural biology. Solid-state NMR (ssNMR) has made possible atomic-level structural studies of large, insoluble, and non-crystalline biological systems, such as amyloid fibrils and membrane proteins.
Amyloid fibrils are associated with at least 20 human diseases, making structural aspects of their formation crucial to understanding their aggregation pathways. Huntington’s disease (HD) is caused by an expansion beyond a threshold of the polyglutamine (polyQ) domain in the Exon 1 of the huntingtin protein (htt). The 17-residue N-terminal segment of the Exon 1 (httNT) initiates the fibril aggregation and helps stabilize oligomers and fibrils. On the contrary, a polyPro segment C-terminal to the polyQ reduces fibril aggregation. In this thesis, magic-angle spinning (MAS) ssNMR was used to elucidate atomic-resolution structure and dynamics of the polyQ and its flanking domains in polyQ-containing amyloid-like fibrils.
More than 25% of human proteins are membrane proteins. Caveolin-1 (Cav1) is a protein found associated with cholesterol-rich membranes that forms caveolae, curved cave-like invaginations in the plasma membrane, and is implicated in muscular diseases and cancers. The caveolin-scaffolding domain (CSD) of Cav1 is responsible for cholesterol-recognition and oligomerization to form the caveolae. In this thesis, MAS and static ssNMR are used to elucidate molecular structure of the CSD and its perturbation of the lipid bilayer in a cholesterol-rich lipid environment. These results allow for a more thorough understanding of the role of CSD in caveolae formation.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Hoop, Codyclh104@pitt.eduCLH1040000-0003-4441-8321
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis Advisorvan der Wel, Patrickpvdwel@pitt.eduPVDWEL
Committee Chairvan der Wel, Patrickpvdwel@pitt.eduPVDWEL
Committee MemberHorne, W. Sethhorne@pitt.eduHORNE
Committee MemberIshima, Riekoishima@pitt.eduISHIMA
Committee MemberThibodeau, Patrick H.thibodea@pitt.eduTHIBODEA
Committee MemberWetzel, Ronaldrwetzel@pitt.eduRWETZEL
Date: 11 December 2014
Date Type: Publication
Defense Date: 24 November 2014
Approval Date: 11 December 2014
Submission Date: 11 December 2014
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 196
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Biophysics and Structural Biology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: polyglutamine, Huntington's disease, amyloid, caveolin, membrane proteins, solid-state NMR
Date Deposited: 11 Dec 2014 15:49
Last Modified: 15 Nov 2016 14:26


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