# Structure and Function of Desmosomal Cadherins

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $447,858

## Abstract

Project Summary
Desmosomes are intercellular junctions that impart strength to tissues by connecting the intermediate filament
networks of adherent cells. Members of two cadherin subfamilies, the desmogleins and desmocollins, mediate
desmosomal adhesion in the extracellular space. While electron microscopy analyses reveal a structure with
apparently high order, the arrangement and interactions of desmocollins and desmogleins that underlie the
extracellular architecture of desmosomes remains unknown. This lack of knowledge has persisted in part due
to the inability to produce functional desmosomal cadherin ectodomains in recombinant expression systems.
Here we present preliminary data in which we present a mammalian expression system in which all seven
human desmosomal cadherin ectodomains are expressed functionally and at high levels; we have determined
crystal structures of ectodomains from desmogleins 2 and 3 and desmocollins 1 and 2; we have biophysically
characterized binding behavior of these proteins, revealing family-wise heterophilic specificity – where
desmogleins only bind to desmocollins, and vice versa. In this proposal we will (1) perform functional
mutagenesis analyses of structurally identified putative cis and trans interface regions, with biophysical and
structural readout; (2) perform cell-based mutagenesis experiments to correlate molecular structural features
with desmosome morphology and function in transfected cells; and (3) produce Cryo-EM tomographic
reconstructions of desmosome-like junctions that spontaneously polymerize from Dsg and Dsc extracellular
domains between adherent liposome membranes. Overall, this work will provide an atomic-level understanding
of desmosome extracellular architecture.

## Key facts

- **NIH application ID:** 9878878
- **Project number:** 5R01GM118584-04
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** LAWRENCE S SHAPIRO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $447,858
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9878878

## Citation

> US National Institutes of Health, RePORTER application 9878878, Structure and Function of Desmosomal Cadherins (5R01GM118584-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9878878. Licensed CC0.

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