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.
Highlights
Nervous system function is critically dependent on the underlying neural architecture, including patterns of neuronal connectivity
Mutations in PCDH19 cause a female-limited form of infant-onset epilepsy (Dibbens et al, 2008; Scheffer et al, 2008; Depienne and LeGuern, 2012; van Harssel et al, 2013; Leonardi et al, 2014; Thiffault et al, 2016; Terracciano et al, 2016)
The structural and biochemical data presented here provide a first view on the molecular mechanism of Pcdh19 adhesion, which is likely used by all non-clustered d and clustered protocadherins
Summary
Nervous system function is critically dependent on the underlying neural architecture, including patterns of neuronal connectivity. The cadherin superfamily is a large and diverse family of cell adhesion molecules that are strongly expressed in the developing nervous system (Hirano and Takeichi, 2012; Suzuki, 1996; Frank and Kemler, 2002; Shapiro et al, 2007; Gumbiner, 2005;Chen and Maniatis, 2013). The differential expression of classical cadherins and protocadherins, the largest groups within the cadherin superfamily, suggests that they play important roles in the development of neural circuitry (Weiner and Jontes, 2013; Hirano and Takeichi, 2012), an idea supported by their involvement in a range of neurodevelopmental disorders (Redies et al, 2012; Hirabayashi and Yagi, 2014). The non-clustered d-protocadherins have been linked to autism spectrum disorders, intellectual disability, congenital microcephaly and epilepsy.
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