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Proc Natl Acad Sci U S A. 2019 Sep 24;116(39):19717-19726. doi: 10.1073/pnas.1909989116. Epub 2019 Aug 26.

Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly.

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Department of Biochemistry, Duke University, Durham, NC 27710.
Department of Cell Biology, Duke University, Durham, NC 27710.
Department of Microbiology and Molecular Genetics, Duke University, Durham, NC 27710.
Genomics and Medicine, NIM Genetics, 28049 Madrid, Spain.
Department of Pediatric Neurology, Hospital Universitario Quirón, 28223 Madrid, Spain.
Department of Neurology, University of Minnesota, Minneapolis, MN 55454.
Department of Neurobiology, Duke University, Durham, NC 27710.
Department of Pediatrics, Duke University, Durham, NC 27710.
Department of Biochemistry, Duke University, Durham, NC 27710;


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 β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-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 β4-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 β4-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.


axon initial segment; giant ankyrin-G; neurodevelopmental mutation; phosphorylation; β-4 spectrin

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