| First Author | Yang R | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 39 | Pages | 19717-19726 |
| PubMed ID | 31451636 | Mgi Jnum | J:279401 |
| Mgi Id | MGI:6362352 | Doi | 10.1073/pnas.1909989116 |
| Citation | Yang R, et al. (2019) Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly. Proc Natl Acad Sci U S A 116(39):19717-19726 |
| abstractText | 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 beta4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of beta4-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 beta4-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 beta4-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. |
