PUBLICATION

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

Authors
Cooper, S.R., Jontes, J.D., Sotomayor, M.
ID
ZDB-PUB-161028-3
Date
2016
Source
eLIFE   5: (Journal)
Registered Authors
Jontes, James
Keywords
biophysics, human, neuroscience, structural biology, zebrafish
MeSH Terms
  • Animals
  • Brain/embryology
  • Cadherins/chemistry*
  • Cadherins/metabolism*
  • Crystallography, X-Ray
  • Epilepsy/genetics
  • Epilepsy/physiopathology
  • Humans
  • Models, Molecular
  • Mutant Proteins/genetics
  • Mutation, Missense
  • Protein Binding
  • Protein Conformation
  • Zebrafish
  • Zebrafish Proteins/chemistry*
  • Zebrafish Proteins/metabolism*
PubMed
27787195 Full text @ Elife
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping