Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases
Abstract
Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity. Non-clustered δ1 protocadherins form a cadherin subgroup of proteins with seven extracellular cadherin (EC) repeats and cytoplasmic domains distinct from those of classical cadherins. Non-clustered δ1 protocadherins mediate homophilic adhesion and have been implicated in various diseases including asthma, autism, and cancer. Here we present X-ray crystal structures of human Protocadherin-1 (PCDH1), a δ1-protocadherin member essential for New World Hantavirus infection that is typically expressed in the brain, airway epithelium, skin keratinocytes, and lungs. The structures suggest a binding mode that involves antiparallel overlap of repeats EC1 to EC4. Mutagenesis combined with binding assays and biochemical experiments validated this mode of adhesion. Overall, these results reveal the molecular mechanism underlying adhesiveness of PCDH1 and δ1-protocadherins, also shedding light on PCDH1’s role in maintaining airway epithelial integrity, the loss of which causes respiratory diseases.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE; Ohio State University; National Institutes of Health (NIH)
- OSTI Identifier:
- 1574156
- Grant/Contract Number:
- AC02-06CH11357; P30 GM124165; S10 RR029205; GUP 49774; 59251
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Communications Biology
- Additional Journal Information:
- Journal Volume: 2; Journal Issue: 1; Journal ID: ISSN 2399-3642
- Publisher:
- Springer Nature
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; molecular neuroscience; respiratory tract diseases; x-ray crystallography
Citation Formats
Modak, Debadrita, and Sotomayor, Marcos. Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases. United States: N. p., 2019.
Web. doi:10.1038/s42003-019-0586-0.
Modak, Debadrita, & Sotomayor, Marcos. Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases. United States. https://doi.org/10.1038/s42003-019-0586-0
Modak, Debadrita, and Sotomayor, Marcos. Mon .
"Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases". United States. https://doi.org/10.1038/s42003-019-0586-0. https://www.osti.gov/servlets/purl/1574156.
@article{osti_1574156,
title = {Identification of an adhesive interface for the non-clustered δ1 protocadherin-1 involved in respiratory diseases},
author = {Modak, Debadrita and Sotomayor, Marcos},
abstractNote = {Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity. Non-clustered δ1 protocadherins form a cadherin subgroup of proteins with seven extracellular cadherin (EC) repeats and cytoplasmic domains distinct from those of classical cadherins. Non-clustered δ1 protocadherins mediate homophilic adhesion and have been implicated in various diseases including asthma, autism, and cancer. Here we present X-ray crystal structures of human Protocadherin-1 (PCDH1), a δ1-protocadherin member essential for New World Hantavirus infection that is typically expressed in the brain, airway epithelium, skin keratinocytes, and lungs. The structures suggest a binding mode that involves antiparallel overlap of repeats EC1 to EC4. Mutagenesis combined with binding assays and biochemical experiments validated this mode of adhesion. Overall, these results reveal the molecular mechanism underlying adhesiveness of PCDH1 and δ1-protocadherins, also shedding light on PCDH1’s role in maintaining airway epithelial integrity, the loss of which causes respiratory diseases.},
doi = {10.1038/s42003-019-0586-0},
journal = {Communications Biology},
number = 1,
volume = 2,
place = {United States},
year = {Mon Sep 30 00:00:00 EDT 2019},
month = {Mon Sep 30 00:00:00 EDT 2019}
}
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Protocadherin-19 and N-cadherin interact to control cell movements during anterior neurulation
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Protocadherins control the modular assembly of neuronal columns in the zebrafish optic tectum
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Works referencing / citing this record:
Family-wide Structural and Biophysical Analysis of Binding Interactions among Non-clustered δ-Protocadherins
journal, February 2020
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