# Nanoscale structure and function of desmosomes

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $323,433

## Abstract

Project Summary
The epidermis provides protection from environmental insult, dehydration and stress. Mechanical strength is
derived from robust cell-cell adhesive junctions called desmosomes is a fundamental feature of epidermal
tissue. Desmosomes are macromolecular complexes composed of desmosomal cadherins, which mediate cell-
cell adhesion, and a number of intracellular plaque proteins, including desmoplakin, which couples the complex
to the intermediate filament cytoskeleton. Notably, aberrant desmosome function can lead to severe epidermal
disorders. Pemphigus vulgaris is a potentially life-threatening skin blistering disease caused by autoantibodies
directed against the desmosomal cadherin desmoglein-3 (Dsg3) that leads to disruption of cell-cell adhesion.
Though responsible for mechanical integrity, desmosomes can switch between strong and weak states in
development and wound healing. This functional transition occurs with minimal change to the core proteins
comprising the desmosome. We hypothesize that the architecture or organization of proteins within a
desmosome drives its adhesive function. However, due to the size and molecular complexity of desmosomes
there is a lack of tools to study this structure-function relationship creating a critical barrier in this field. We will
use a multi-disciplinary approach to address this challenge and to test the hypothesis that the biophysical
organization of proteins in the desmosome provides a mechanism to regulate adhesion. We recently
developed two highly innovative and complimentary super-resolution fluorescence microscopy approaches to
study the order and organization of proteins within desmosomes. Our goal is to elucidate how the order and
organization of proteins impacts the adhesive function of desmosomes in healthy and disease states. This will
provide novel insight into the structure and function of these critical complexes. In Aim 1 we will determine the
how the organization of plaque proteins changes in different adhesive states with the goal of identifying
functionally sensitive elements and potential biomarkers. In Aim 2 we will use a live cell approach to study
mechanisms that confer ordering of desmosomal cadherins, and how this order is altered with function. Finally,
in Aim 3 we will define changes to the architecture of the desmosome induced in pemphigus vulgaris, with the
goal of facilitating development of targeted therapeutics. We will use primary human keratinocytes and human
tissue biopsy samples to address these questions. Accomplishment of these goals will provide a fundamental
understanding and framework of how protein organization and dynamics influence the adhesive function of
desmosomes in healthy and disease states.

## Key facts

- **NIH application ID:** 10380815
- **Project number:** 5R01AR072697-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Alexa Lynn Mattheyses
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $323,433
- **Award type:** 5
- **Project period:** 2018-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10380815

## Citation

> US National Institutes of Health, RePORTER application 10380815, Nanoscale structure and function of desmosomes (5R01AR072697-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10380815. Licensed CC0.

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