Recent studies have yielded exciting new insights into AIS physiology, the molecular organization of the AIS, and AIS-regulated protein trafficking 12, 13. Pathogenic variants of ANK3 and SPTBN4 (the genes encoding AnkG and β4 spectrin proteins in humans, respectively) lead to severe intellectual disability and neuropathy 8, 9, while injuries and diseases may be accompanied by rapid calpain-dependent proteolysis of AnkG and β4 spectrin 10, 11. For example, loss of AnkG blocks clustering of Na + and K + channels 5, 6, and AnkG-deficient axons acquire dendritic features, including spines and post-synaptic densities 7.
These properties depend on the cytoskeletal and scaffolding proteins AnkyrinG (AnkG) and β4 spectrin.
They have two main functions: to cluster and maintain ion channels in high densities for efficient action potential initiation 1, and to control neuronal polarity by regulating the differential distribution and trafficking of proteins, vesicles, organelles, and even lipids between axonal and somatodendritic compartments 2, 3, 4. Our results provide conceptual insights and a resource for AIS molecular organization, the mechanisms of AIS stability, and polarized trafficking in neurons.Īxon initial segments (AISs) are located at the interface between somatodendritic and axonal domains of neurons. We show many are located at the AIS, interact with known AIS proteins, and their loss disrupts AIS structure and function. Our experiments reveal a diverse set of biotinylated proteins not previously reported at the AIS.
We target the biotin-ligase BirA* to the AIS by generating fusion proteins of BirA* with NF186, Ndel1, and Trim46 these chimeras map the molecular organization of AIS intracellular membrane, cytosolic, and microtubule compartments. Here, we use proximity biotinylation and mass spectrometry to identify the AIS proteome. While the mechanisms of AIS Na + and K + channel clustering are understood, the molecular mechanisms that stabilize the AIS and control neuronal polarity remain obscure. Axon initial segments (AISs) generate action potentials and regulate the polarized distribution of proteins, lipids, and organelles in neurons.
0 kommentar(er)
