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An Adhesive Interface for the Non-Clustered δ1 Protocadherin-1 Involved in Respiratory Diseases

Debadrita Modak, Marcos Sotomayor
doi: https://doi.org/10.1101/498196
Debadrita Modak
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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Marcos Sotomayor
1Department of Chemistry and Biochemistry, The Ohio State University, 484 W 12th Avenue, Columbus, OH 43210
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  • For correspondence: sotomayor.8@osu.edu
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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. The 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 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 16, 2018.
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An Adhesive Interface for the Non-Clustered δ1 Protocadherin-1 Involved in Respiratory Diseases
Debadrita Modak, Marcos Sotomayor
bioRxiv 498196; doi: https://doi.org/10.1101/498196
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An Adhesive Interface for the Non-Clustered δ1 Protocadherin-1 Involved in Respiratory Diseases
Debadrita Modak, Marcos Sotomayor
bioRxiv 498196; doi: https://doi.org/10.1101/498196

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