Advisor(s)
Alexa Mattheyses
Committee Member(s)
Chenbei Chang
Susan Bellis
School
Joint Health Sciences (Interdisciplinary)
Document Type
Thesis
Department (new version)
Joint Health Sciences
Date of Award
9-9-2024
Abstract
UNCOVERING THE CONTRIBUTION OF DESMOPLAKIN ISOFORMS TO DESMOSOME STRUCTURE AND FUNCTION KRISHNA PATEL MULTIDISCIPLINARY BIOMEDICAL SCIENCE ABSTRACT Desmosomes are cell-cell junctions that maintain the integrity of tissues that experience significant mechanical stress, such as the skin and heart. Desmosomal plaque proteins are connected to the intermediate filaments by desmoplakin (DP), and genetic variants in DP are associated with several skin and heart pathologies, including erythrokeratodermia and arrhythmogenic cardiomyopathy. DP contains three domains: an N-terminal plakin head, a central rod, and an intermediate filament-binding C-terminal tail. Furthermore, DP has three splice isoforms (DPI, DPIa, and DPII) that differ only in the length of the rod domain and have distinct tissue-specific expression patterns. DPI is the primary cardiac isoform and is present in all desmosomes, whereas DPIa and DPII are expressed in stratified epithelia. Although DP’s binding partners and spliced isoforms are known, their spatial arrangement and functional implications within the desmosome remain unclear. The largest isoform, DPI, has a head to tail length of 180 nm. Previous work suggests that the long axis of DP is arranged not perpendicular to the plasma membrane but at an acute angle. However, it is unclear if the length of the rod domain influences the architecture of DP. In this project, we established individual EGFP-tagged isoforms (DPI-mEGFP, DPIa-mEGFP, and DPII-mEGFP) in DP-knockout human epidermal keratinocytes (HaCaTs) containing varying DP rod domain lengths. In these stable cell lines, DP architecture has been quantified by super-resolution STORM microscopy, and desmosome adhesive strength has been evaluated by dispase assay. Together, this work sets the stage to understand how DP structure guides desmosome function through the regulation of junction strength by differentially expressed desmoplakin isoforms. Keywords: Desmosome, Desmoplakin, STORM
ProQuest ID
Recommended Citation
Patel, Krishna, "Uncovering The Contribution Of Desmoplakin Isoforms To Desmosome Structure And Function" (2024). All ETDs from UAB. 7581.
https://digitalcommons.library.uab.edu/etd-collection/7581
