Format

Send to

Choose Destination
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.

Author information

1
Department of Biochemistry, Duke University, Durham, NC 27710.
2
Department of Cell Biology, Duke University, Durham, NC 27710.
3
Department of Microbiology and Molecular Genetics, Duke University, Durham, NC 27710.
4
Genomics and Medicine, NIM Genetics, 28049 Madrid, Spain.
5
Department of Pediatric Neurology, Hospital Universitario Quirón, 28223 Madrid, Spain.
6
Department of Neurology, University of Minnesota, Minneapolis, MN 55454.
7
Department of Neurobiology, Duke University, Durham, NC 27710.
8
Department of Pediatrics, Duke University, Durham, NC 27710.
9
Department of Biochemistry, Duke University, Durham, NC 27710; vann.bennett@duke.edu.

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 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.

KEYWORDS:

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

PMID:
31451636
DOI:
10.1073/pnas.1909989116
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center