Structural determinants of adhesion by Protocadherin-19 and implications for its role in epilepsy
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
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Crystal Structure of Zebrafish Protocadherin-19 EC3-4Publicly available at the RCSB databanks (at time of publication).
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Crystal Structure of Zebrafish Protocadherin-19 EC1-4Publicly available at the RCSB databanks (at time of publication).
Article and author information
Author details
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.
Reviewing Editor
- William I Weis, Stanford University Medical Center, United States
Version history
- Received: June 6, 2016
- Accepted: October 25, 2016
- Accepted Manuscript published: October 27, 2016 (version 1)
- Version of Record published: November 18, 2016 (version 2)
Copyright
© 2016, Cooper et al.
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.
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