The PNAS Dynasty team revealed the molecular structure mechanisms of nerve cell polarity maintenance.

As the basic structure and functional unit of nervous system, nerve cells are a kind of highly polarized cells. Typical nerve cells are composed of dendrites, cell bodies and axons that transmit signals.different materials constitute different morphology and unique physiological functions of dendrites, cell bodies and axons, so as to maintain the polarity of nerve cells.the axon initial segment (axon initial segment) of nerve cells was observed, AIS is a specific membrane structure region near the cell body near the axon, which is rich in a large number of voltage-gated sodium channels (NAV) Channel, voltage-gated potassium channel (KCNQ2 / 3), cell adhesion molecules (nfasc, NrCAM, etc.) and a variety of scaffold proteins and cytoskeleton proteins are important sites for nerve cells to integrate the input signals of soma and dendrites, and regulate and generate action potential [1,2].as the most important protein complex organizer in AIS, ankyrin-G is a landmark protein of AIS.ankyrin-G anchors a variety of ion channels and cell adhesion molecules to the cell membrane, thus ensuring the integrity and stability of the structure and function of AIS [3].at the same time, the special location of the axon initiation segment makes ankyrin-G act as a specific "gatekeeper", maintaining the axon dendrite polarity of nerve cells by selectively regulating the proteins and specific organelles entering the axon [4-6]. However, the molecular basis of this selective regulatory substance in and out of the axon is still unclear.on December 30, 2019, the Key Laboratory of membranous organelles and cell dynamics of the Ministry of education, the National Research Center for micro scale material science and the school of life sciences of the University of science and technology of China published an online publication entitled "mechanical insights into the interactions of dynein regulator Ndel1 with neural ankyrins and "Implication in polarity maintenance" 【7】 Through comprehensive use of Biochemistry, structural biology, chemical biology and molecular neurocytobiology, we revealed the molecular mechanism of Ndel1 / ankyrin-G complex regulating substances selectively entering axons at the beginning of neuraxon process, thus maintaining the polarity of nerve cells. This is the molecular mechanism of Ndel1 / ankyrin-G complex in NAT Chem in 2018 BIOL published a series of research results around the ankyrin family proteins after the identification of regulatory cell autophagy peptides in ankyrin family proteins [8].Ndel1 is a regulatory protein of motor dynein complex, which is an important intracellular molecule. Previous studies have shown that Ndel1 undergoes a reorientation process from around the centromere to the beginning of axon in the early stage of neural cell development and differentiation, which suggests that Ndel1 may have a direct interaction with ankyrin-G [9].in this study, the direct interaction between ankyrin-G and Ndel1 was determined by biochemical experiments in vitro, and the quantitative binding capacity was detected by ITC. The minimum binding region of two proteins was determined by systematically comparing the dissociation constants of the two proteins.interestingly, they found that ankyrin-G binds to Ndel1 in a ratio of 1:2, which is consistent with the fact that Ndel1 functions as a dimer in vivo.subsequently, they found that ankyrin-B, the homologous protein of ankyrin-G, could also bind Ndel1 in a ratio of 1:2, and analyzed the high-resolution crystal structure of ankyrin-B / Ndel1 complex, and elaborated the molecular mechanism of ankyrin-G / ankyrin-B binding to Ndel1.then they specifically knocked out ankyrin-G in the hippocampal neurons of mice, and found that Ndel1 also lost the specific location of AIS. After the wild-type ankyrin-G was supplemented, Ndel1 was relocated to AIS again, which suggested that Ndel1 specific localization depended on its interaction with ankyrin-g.finally, based on the biochemical and structural information, the researchers designed a peptide specifically binding to Ndel1 derived from ankyrin-g. the peptide was transferred into mouse hippocampal neurons as a tool to break the endogenous ankyrin-G / Ndel1 complex. It was found that the peptide changed the localization of Ndel1 originally located in AIS and destroyed the selective transport of axonal materials into the hippocampus of mice The protein located in the cell body and dendrite can enter the axon through AIS.this finding suggests that the Ndel1 / ankyrin-G complex can selectively prevent non axonal goods from entering the axon at the beginning of axon, thus maintaining the polarity of nerve cells.it is reported that Ye Jin, a doctoral student from the school of life of CUHK, and Professor Li Jianchao, School of medicine, South China University of technology, are the co first authors of the paper, and Professor Dai of the school of life of CUHK is the corresponding author of the paper.the research group of academician Zhang Mingjie of Hong Kong University of science and technology and Professor Zhang Yan's research group of School of life sciences of Peking University have also been greatly helped.original link: plate maker: xiaoxianzi, references 1. M. n. rasban, the axon initial segment and the maintenance of neural polarity.Nat . Rev. Neurosci. 11, 552–562 (2010).2. J. T.Kevenaar, C. C. Hoogenraad, The axonal cytoskeleton: From organization tofunction. Front. Mol. Neurosci. 8, 44 (2015).3. K. L. Hedstrom, Y. Ogawa, M. N. Rasband,AnkyrinG is required for maintenance of the axon initial segment and neuronalpolarity. J. Cell Biol. 183, 635–640 (2008).4. C. Nakada et al., Accumulation of anchored proteins formsmembrane diffusion barriers during neuronal polarization. Nat. Cell Biol. 5,626–632 (2003).5. B.Winckler, P. Forscher, I. Mellman, A diffusion barrier maintains distributionof membrane proteins in polarized neurons. Nature 397, 698–701 (1999).6. C. Leterrier et al., Nanoscalearchitecture of the axon initial segment reveals an or- ganized and robustscaffold. Cell Rep. 13, 2781–2793 (2015).7. J. Ye, et al., Mechanisticinsights into the interactions of dynein regulator Ndel1 with neuronal ankyrinsand implications in polarity maintenance. PNAS (2019) 8. J. Li, et al., Potent and specific Atg8-targetingautophagy inhibitory peptides from giant ankyrins. Nat Chem Biol. 14, 778-787 (2018).9. M. Kuijpers et al., Dynein regulator NDEL1 controlspolarized cargo transport at the axon initial segment. Neuron 89, 461–471(2016).