Heier, Jonathon
(2021)
The Biochemical Characterization of Alpha-T-Catenin Ligand Binding.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cell-cell junctions allow cells to maintain structure, organize into complex tissues and organs, and communicate both physically and chemically to function in unique environments. One such environment is the heart where cells must maintain adhesion during coordinated and constant rhythmic contraction. It is estimated that cardiomyocytes experience forces in excess of 1000nN, more than ten times that of nonmotile epithelial cells. It is not clear how these cells maintain adhesion under such extreme force. One of the cellular complexes involved in cardiomyocyte adhesion is the fascia adherens, also known as the adherens junction. The adherens junction couples adjacent cardiomyocytes and integrates the contractile myofibril network between them. The primary link between the adherens junction and the F-actin cytoskeleton is alpha-catenin. Two different alpha-catenins are expressed in the mammalian heart and, in the work presented here, I sought to understand how alpha-catenin functions in cardiomyocyte cell-cell adhesion. Specifically, my work addresses the properties of alpha-T(testes)-catenin, a poorly characterized isoform with expression limited to the testes, central nervous system, and heart. Mutations in alpha-T-catenin have been linked to cardiomyopathy and I sought to characterize its unique interactions with other adhesion and cytoskeletal proteins in the context of cardiomyocytes. I found that, in contrast to the better characterized alpha-E(epithelial)-catenin, alpha-T-catenin is a monomer in solution and can readily bind F- actin in the absence of tension. I also found that both alpha-E-catenin and alpha-T-catenin bind to beta-catenin at the adherens junction with similar affinities. Finally, I showed that alpha-T-catenin binds to vinculin by a tension-dependent mechanism, but autoinhibition of the M-region is regulated by a distinct mechanism of intramolecular interaction involving the alpha-T-catenin N-terminal domain. These unique properties of alpha-T-catenin will help to define its function in cardiomyocytes and offer insight into how mutations in alpha-T-catenin contribute to cardiomyopathy.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
29 July 2021 |
| Defense Date: |
12 July 2021 |
| Approval Date: |
15 September 2021 |
| Submission Date: |
29 July 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
161 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cell Biology and Molecular Physiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Cell-cell adhesion, Adherens Junction, Alpha-catenin |
| Date Deposited: |
16 Sep 2021 01:26 |
| Last Modified: |
16 Sep 2021 01:26 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41526 |
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