Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy

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Data availability
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Abstract

Non-clustered δ-protocadherins are homophilic cell adhesion molecules essential for the development of the vertebrate nervous system, as several are closely linked to neurodevelopmental disorders. Mutations in protocadherin-19 (PCDH19) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations in PCDH19 have been identified in patients with PCDH19-FE, about half of which are missense mutations in the adhesive extracellular domain. Neither the mechanism of homophilic adhesion by PCDH19, nor the biochemical effects of missense mutations are understood. Here we present a crystallographic structure of the minimal adhesive fragment of the zebrafish Pcdh19 extracellular domain. This structure reveals the adhesive interface for Pcdh19, which is broadly relevant to both non-clustered δ and clustered protocadherin subfamilies. In addition, we show that several PCDH19-FE missense mutations localize to the adhesive interface and abolish Pcdh19 adhesion in in vitro assays, thus revealing the biochemical basis of their pathogenic effects during brain development.

Data availability

The following data sets were generated

1. Cooper
2. SR; Jontes
3. JD; Sotomayor
4. M.
(2015) Crystal Structure of Zebrafish Protocadherin-19 EC3-4
Publicly available at the RCSB databanks (at time of publication).

http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5CO1
1. Cooper
2. SR; Jontes
3. JD; Sotomayor
4. M.
(2016) Crystal Structure of Zebrafish Protocadherin-19 EC1-4
Publicly available at the RCSB databanks (at time of publication).

http://www.rcsb.org/pdb/search/structidSearch.do?structureId=5IU9

Article and author information

Author details

Sharon R Cooper

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States

Competing interests
The authors declare that no competing interests exist.
James D Jontes

Department of Neuroscience, The Ohio State University, Columbus, United States

For correspondence
jontes.1@osu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8954-6127
Marcos Sotomayor

Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States

For correspondence
sotomayor.8@osu.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3333-1805

Funding

National Institutes of Health (R21MH09463)

James D Jontes

Ohio State University

Marcos Sotomayor

National Institutes of Health (P41 GM103403)

Marcos Sotomayor

National Institutes of Health (S10 RR029205)

Marcos Sotomayor

Department of Energy (GUP 40277)

Marcos Sotomayor

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.