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?-Protocadherin structural diversity and functional implications.

ABSTRACT: Stochastic cell-surface expression of ?-, ?-, and ?-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse ?-Pcdhs ?A1, ?A8, ?B2, and ?B7 revealing trans-homodimers, and of C-terminal ectodomain fragments from ?-Pcdhs ?A4 and ?B2, which depict cis-interacting regions in monomeric form. Together these structures span the entire ?-Pcdh ectodomain. The trans-dimer structures reveal determinants of ?-Pcdh isoform-specific homophilic recognition. We identified and structurally mapped cis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from ?B-subfamily isoforms formed cis dimers, whereas ?A isoforms did not, but both ?A and ?B isoforms could interact in cis with ?-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the ?-Pcdh trans interface, and suggest that subfamily- or isoform-specific cis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.

SUBMITTER: Goodman KM

PROVIDER: S-EPMC5106212 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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γ-Protocadherin structural diversity and functional implications.

Goodman Kerry Marie KM Rubinstein Rotem R Thu Chan Aye CA Mannepalli Seetha S Bahna Fabiana F Ahlsén Göran G Rittenhouse Chelsea C Maniatis Tom T Honig Barry B Honig Barry B Shapiro Lawrence L

eLife 20161026

Stochastic cell-surface expression of α-, β-, and γ-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse γ-Pcdhs γA1, γA8, γB2, and γB7 revealing <i>trans</i>-homodimers, and of C-terminal ectodomain fragments from γ-Pcdhs γA4 and γB2, which depict <i>cis</i>-interacting regions in monomeric form. Together these s ...[more]

PMID: 27782885

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Project description:BACKGROUND: The synaptic cell adhesion molecules, protocadherins, are a vertebrate innovation that accompanied the emergence of the neural tube and the elaborate central nervous system. In mammals, the protocadherins are encoded by three closely-linked clusters (alpha, beta and gamma) of tandem genes and are hypothesized to provide a molecular code for specifying the remarkably-diverse neural connections in the central nervous system. Like mammals, the coelacanth, a lobe-finned fish, contains a single protocadherin locus, also arranged into alpha, beta and gamma clusters. Zebrafish, however, possesses two protocadherin loci that contain more than twice the number of genes as the coelacanth, but arranged only into alpha and gamma clusters. To gain further insight into the evolutionary history of protocadherin clusters, we have sequenced and analyzed protocadherin clusters from the compact genome of the pufferfish, Fugu rubripes. RESULTS: Fugu contains two unlinked protocadherin loci, Pcdh1 and Pcdh2, that collectively consist of at least 77 genes. The fugu Pcdh1 locus has been subject to extensive degeneration, resulting in the complete loss of Pcdh1gamma cluster. The fugu Pcdh genes have undergone lineage-specific regional gene conversion processes that have resulted in a remarkable regional sequence homogenization among paralogs in the same subcluster. Phylogenetic analyses show that most protocadherin genes are orthologous between fugu and zebrafish either individually or as paralog groups. Based on the inferred phylogenetic relationships of fugu and zebrafish genes, we have reconstructed the evolutionary history of protocadherin clusters in the teleost fish lineage. CONCLUSION: Our results demonstrate the exceptional evolutionary dynamism of protocadherin genes in vertebrates in general, and in teleost fishes in particular. Besides the 'fish-specific' whole genome duplication, the evolution of protocadherin genes in teleost fishes is influenced by lineage-specific gene losses, tandem gene duplications and regional sequence homogenization. The dynamic protocadherin clusters might have led to the diversification of neural circuitry among teleosts, and contributed to the behavioral and physiological diversity of teleosts.

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?-Protocadherin structural diversity and functional implications.

Publications

γ-Protocadherin structural diversity and functional implications.

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