Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.
Proc Natl Acad Sci U S A
; 116(39): 19717-19726, 2019 09 24.
Article
em En
| MEDLINE
| ID: mdl-31451636
ABSTRACT
Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and ß4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of ß4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of N- and C-terminal domains to an extended state that is required for binding and recruitment of ß4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of ß4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Anquirinas
/
Segmento Inicial do Axônio
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article