WU, NAN
(2019)
An insight into an autophagy receptor p62 oligomerization through PB1 domain using molecular modeling.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
Autophagy is a term of the ancient process in eukaryotic cells, which is responsible for transporting and degrading the ‘bad proteins’ to promote the cell survival. The Nobel Assembly at Karolinska Institute awarded the 2016 Nobel Prize in Physiology or Medicine to Yoshinori Ohsumi for his discoveries of mechanisms for autophagy. Autophagy has been reported to be related to the regulation of cancer and the neurodegenerative diseases. p62/sequestosome1 (SQSTM1), an autophagy inducer brought about innovative ideas about the treatment of those diseases. p62 is a multi-domain protein and each of its domain will have interactions with partners that are involved in the different physiological processes. Our lab is the first one to build the 3D structure of full-length p62 and has designed compounds (XIE2008 and XIE62-1004) as p62 regulator with experiments published in Nature Communications. In this thesis, to address three questions: 1) How p62 PB1-p62 PB1 oligomerized? 2) How newer p62-ZZ compound affect p62 oligomerization? 3) What is the role of second-generation p62-ZZ compound(s) for this process? Firstly, the author briefly discussed the relationship among autophagy, p62 and different kinds of diseases such as Alzheimer’s disease (AD), in Parkinson’s disease (PD) and Huntington's disease (HD). Secondly, the author validated published 3D model of full-length of p62 via docking with its partners separately. Importantly, one of p62 domains called PB1 does self-oligomerization and innovative prediction study of the binding conformations between two p62s using Z-DOCK, a rigid-body docking program is discussed. The author constructed p62 PB1-p62 PB1 oligomerization through protein-protein docking and selected the most possible conformation of p62 PB1-p62 PB1 oligomerization. The author selected the most important interacted residues for bio-assay validation.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
3 April 2019 |
| Date Type: |
Publication |
| Defense Date: |
18 March 2019 |
| Approval Date: |
3 April 2019 |
| Submission Date: |
2 April 2019 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
81 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Computer-aided Drug Design (CADD), Docking, Autophagy, p62, PB1-PB1 oligomerization, Neurodegenerative disorders |
| Date Deposited: |
03 Apr 2019 15:30 |
| Last Modified: |
03 Apr 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/36215 |
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