Identification of an adhesive interface for the non-clustered \u03b41 protocadherin-1 involved in respiratory diseases

Debadrita Modak,Marcos Sotomayor

doi:10.1038/s42003-019-0586-0

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.

Highlights

Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity
Binding assays determine extracellular cadherin (EC) repeats required for adhesion
To determine which EC repeats are essential for PCDH1 homophilic adhesion we created a library of constructs from the human protein by deleting EC repeats from the C- and Nterminus

Summary

Introduction

Cadherins form a large family of calcium-dependent adhesive proteins involved in morphogenesis, cell differentiation, and neuronal connectivity. Cadherins are calcium-dependent adhesion glycoproteins involved in a variety of biological processes such as cell differentiation and tissue morphogenesis[5], cell signaling[6,7,8], mechanotransduction[9,10,11], and brain morphogenesis and wiring[12,13,14,15,16] These proteins have a unique structure including tandem extracellular cadherin (EC) repeats[5,17,18], followed by a transmembrane and a cytoplasmic domain. The δ-protocadherins have seven (δ1) or six (δ2) EC repeats, a single transmembrane helix, and a cytoplasmic domain containing highly conserved motifs of unclear function (CM1, CM2, and CM3 in δ1; CM1 and CM2 in δ2)[19,20] These play a major role in neuronal tissue connectivity and brain wiring and are involved in various neurological disorders such as epilepsy, autism, and schizophrenia[20,21,22]

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