title: 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 inprotocadherin-19(PCDH19) result in a female-limited, infant-onset form of epilepsy (PCDH19-FE). Over 100 mutations inPCDH19have 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 inin vitroassays, thus revealing the biochemical basis of their pathogenic effects during brain development.
authors: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States.|Department of Neuroscience, The Ohio State University, Columbus, United States.
authors: Sharon R
authors: SR
authors: Cooper
authors: Department of Neuroscience, The Ohio State University, Columbus, United States.
authors: James D
authors: 0000-0002-8954-6127
authors: JD
authors: Jontes
authors: Department of Chemistry and Biochemistry, The Ohio State University, Columbus, United States.
authors: Marcos
authors: 0000-0002-3333-1805
authors: M
authors: Sotomayor
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004827:Epilepsy / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000235:genetics; D020125:Mutation, Missense; D011485:Protein Binding; D011487:Protein Conformation; D000091363:Protocadherins; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D015820:Cadherins; D050505:Mutant Proteins; C545892:Pcdh19 protein, zebrafish; D000091363:Protocadherins; D029961:Zebrafish Proteins
keywords: biophysics; cadherin; calcium binding protein; epilepsy; human; intercellular adhesion molecules; neural circuitry; neuroscience; structural biology; zebrafish