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

Rui Yang, Kathryn K. Walder-Christensen, Samir Lalani, Haidun Yan, Irene Díez García-Prieto, Sara Álvarez, Alberto Fernández-Jaén, Laura Speltz, Yong Hui Jiang, Vann Bennett

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


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 Nand 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.

Original languageEnglish (US)
Pages (from-to)19717-19726
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 24 2019

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank E. Robinson and J. Hostettler for technical assistance, J. Cheong for data analysis, and Dr. Erik Soderblom and Dr. Greg Waitt at Duke University School of Medicine Proteomics and Metabolomics Shared Resource for providing the MS/MS service. This work was supported by the Howard Hughes Medical Institute and a George Barth Geller endowed professorship (V.B.), and National Institutes of Health grants R21MH115155 (V.B.) and F31NS096848 (K.K.W.-C.).

Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.


  • Axon initial segment
  • Giant ankyrin-G
  • Neurodevelopmental mutation
  • Phosphorylation
  • β-4 spectrin


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