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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Yang, R; Walder-Christensen, KK; Lalani, S; Yan, H; García-Prieto, ID; Álvarez, S; Fernández-Jaén, A; Speltz, L; Jiang, Y-H; Bennett, V

Published Date

  • September 24, 2019

Published In

Volume / Issue

  • 116 / 39

Start / End Page

  • 19717 - 19726

PubMed ID

  • 31451636

Pubmed Central ID

  • PMC6765234

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1909989116


  • eng

Conference Location

  • United States