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Temple University

1. Beauparlant, Stephen Lewis. Functional characterization of the p97 adaptor protein UBXD1.

Degree: PhD, 2011, Temple University

Molecular Biology and Genetics

p97 is a member of the AAA family of proteins (ATPase Associated with various cellular Activities). It is a highly conserved and abundant protein and functions in numerous ubiquitin-mediated processes including ERAD. Endoplasmic Reticulum Associated Degradation is the process by which misfolded/ubiquitinated proteins translocate out of the ER and migrate to the proteasome for degradation. p97 maintains substrate misfolding and mediates its exit from the ER and trafficking to the 26S proteasome. It also plays important roles in protein trafficking, the cell-cycle, apoptosis and homeotypic Golgi Apparatus and Endoplasmic Reticulum membrane fusion after mitosis. In addition, p97 plays a role in the aggresome-autophagy degradation pathway, which handles the ubiquitin-mediated destruction of aggregate-prone, misfolded, cytosolic proteins. p97 mutation is the causative alteration in the disorder, IBMPFD, which is marked by defects in autophagy. This broad diversity of function is mediated through p97's interaction with a large group of adaptor proteins. Many of these adaptors harbor both p97 interaction motifs and ubiquitin association domains. However, more than half of known p97 adaptors do not. Their function is largely unknown. UBXD1 is one known adaptor for p97 that does not have a ubiquitin association domain (UBA), and has been shown to have decreased interaction with IBMPFD mutant p97R155H and p97A232E. Recently, it has been suggested to perform a role in protein trafficking, specifically in monoubiquitinated caveolin-1 internalization and trafficking to the endosome. A novel high abundance UBXD1 interacting partner has been identified via solution-based mass spectrometric analyses. ERGIC-53, the namesake of the ER-Golgi Intermediate Compartment, has been shown to be involved in bi-directional trafficking between the ER and Golgi. The association between UBXD1 and ERGIC-53 is unique among UBX family members. Deletional analysis has shown that unlike p97, the ERGIC-53-UBXD1 interaction takes place in the extreme amino terminus of UBXD1, (within the first 10 amino acids) which is predicted by computer modeling to form a hydrophobic binding pocket. Further site-directed mutagenesis work has clearly shown four amino acids (3 highly hydrophobic) are crucial for maintaining this interaction. They have been modeled to form a conserved alpha-helix. ßCOPI, a primary member of the COPI coatomer complex which is involved in protectively coating ERGIC-53 positive vesicles, is also thought to be involved with the ERGIC-53-UBXD1-p97 pathway. ßCOPI has been identified as a UBXD1-independent interactor with p97. Modest UBXD1 over- expression using a ponasterone inducible system has shown that UBXD1 modulates ERGIC-53 localization. Additionally, a functional link between UBXD1, p97 and ERGIC-53 in autophagy has been discovered through the use of a highly efficient, miR30-based, inducible knockdown system. Upon individual knockdown of UBXD1, p97 and ERGIC-53, autophagic markers p62 and LC3-II…

Advisors/Committee Members: Grana-Amat, Xavier, Shore, Scott K., Engel, Nora, Buttaro, Bettina A..

Subjects/Keywords: Molecular biology; Autophagy; ERGIC-53; p97; UBXD1

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APA (6th Edition):

Beauparlant, S. L. (2011). Functional characterization of the p97 adaptor protein UBXD1. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,213118

Chicago Manual of Style (16th Edition):

Beauparlant, Stephen Lewis. “Functional characterization of the p97 adaptor protein UBXD1.” 2011. Doctoral Dissertation, Temple University. Accessed October 19, 2019. http://digital.library.temple.edu/u?/p245801coll10,213118.

MLA Handbook (7th Edition):

Beauparlant, Stephen Lewis. “Functional characterization of the p97 adaptor protein UBXD1.” 2011. Web. 19 Oct 2019.

Vancouver:

Beauparlant SL. Functional characterization of the p97 adaptor protein UBXD1. [Internet] [Doctoral dissertation]. Temple University; 2011. [cited 2019 Oct 19]. Available from: http://digital.library.temple.edu/u?/p245801coll10,213118.

Council of Science Editors:

Beauparlant SL. Functional characterization of the p97 adaptor protein UBXD1. [Doctoral Dissertation]. Temple University; 2011. Available from: http://digital.library.temple.edu/u?/p245801coll10,213118

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