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

doi:10.1073/pnas.1909989116

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

Neurology

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36 Scopus citations

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 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 language	English (US)
Pages (from-to)	19717-19726
Number of pages	10
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	116
Issue number	39
DOIs	https://doi.org/10.1073/pnas.1909989116
State	Published - 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.

Keywords

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

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10.1073/pnas.1909989116

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Yang, R., Walder-Christensen, K. K., Lalani, S., Yan, H., García-Prieto, I. D., Álvarez, S., Fernández-Jaén, A., Speltz, L., Jiang, Y. H., & Bennett, V. (2019). Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly. Proceedings of the National Academy of Sciences of the United States of America, 116(39), 19717-19726. https://doi.org/10.1073/pnas.1909989116

Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly. / Yang, Rui; Walder-Christensen, Kathryn K.; Lalani, Samir et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 39, 24.09.2019, p. 19717-19726.

Research output: Contribution to journal › Article › peer-review

Yang, R, Walder-Christensen, KK, Lalani, S, Yan, H, García-Prieto, ID, Álvarez, S, Fernández-Jaén, A, Speltz, L, Jiang, YH & Bennett, V 2019, 'Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 39, pp. 19717-19726. https://doi.org/10.1073/pnas.1909989116

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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 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.",

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AU - Yan, Haidun

AU - García-Prieto, Irene Díez

AU - Álvarez, Sara

AU - Fernández-Jaén, Alberto

AU - Speltz, Laura

AU - Jiang, Yong Hui

AU - Bennett, Vann

N1 - 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.

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N2 - 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.

AB - 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.

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

Abstract

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