Powers Regina M, Hevner Robert F, Halpain Shelley
Department of Neurobiology, School of Biological Sciences, University of California, San Diego, La Jolla, CA, United States.
Sanford Consortium for Regenerative Medicine, La Jolla, CA, United States.
Front Mol Neurosci. 2023 Jan 12;15:1099554. doi: 10.3389/fnmol.2022.1099554. eCollection 2022.
Neuron navigators (Navigators) are cytoskeletal-associated proteins important for neuron migration, neurite growth, and axon guidance, but they also function more widely in other tissues. Recent studies have revealed novel cellular functions of Navigators such as macropinocytosis, and have implicated Navigators in human disorders of axon growth. Navigators are present in most or all bilaterian animals: vertebrates have three Navigators (NAV1-3), has one (Sickie), and has one (Unc-53). Structurally, Navigators have conserved N- and C-terminal regions each containing specific domains. The N-terminal region contains a calponin homology (CH) domain and one or more SxIP motifs, thought to interact with the actin cytoskeleton and mediate localization to microtubule plus-end binding proteins, respectively. The C-terminal region contains two coiled-coil domains, followed by a AAA+ family nucleoside triphosphatase domain of unknown activity. The Navigators appear to have evolved by fusion of N- and C-terminal region homologs present in simpler organisms. Overall, Navigators participate in the cytoskeletal response to extracellular cues microtubules and actin filaments, in conjunction with membrane trafficking. We propose that uptake of fluid-phase cues and nutrients and/or downregulation of cell surface receptors could represent general mechanisms that explain Navigator functions. Future studies developing new models, such as conditional knockout mice or human cerebral organoids may reveal new insights into Navigator function. Importantly, further biochemical studies are needed to define the activities of the Navigator AAA+ domain, and to study potential interactions among different Navigators and their binding partners.
神经元导航蛋白（导航蛋白）是与细胞骨架相关的蛋白质，对神经元迁移、神经突生长和轴突导向很重要，但它们在其他组织中也有更广泛的功能。最近的研究揭示了导航蛋白的新细胞功能，如巨胞饮作用，并表明导航蛋白与人类轴突生长障碍有关。导航蛋白存在于大多数或所有两侧对称动物中：脊椎动物有三种导航蛋白（NAV1 - 3），果蝇有一种（Sickie），线虫有一种（Unc - 53）。在结构上，导航蛋白有保守的N端和C端区域，每个区域都包含特定结构域。N端区域包含一个钙调蛋白同源（CH）结构域和一个或多个SxIP基序，分别被认为与肌动蛋白细胞骨架相互作用并介导定位于微管正端结合蛋白。C端区域包含两个卷曲螺旋结构域，随后是一个活性未知的AAA +家族核苷三磷酸酶结构域。导航蛋白似乎是通过简单生物体中存在的N端和C端区域同源物的融合而进化的。总体而言，导航蛋白与膜运输一起参与细胞骨架对细胞外信号（微管和肌动蛋白丝）的反应。我们提出，液相信号和营养物质的摄取和/或细胞表面受体的下调可能代表了解释导航蛋白功能的一般机制。未来开发新模型（如有条件敲除小鼠或人类大脑类器官）的研究可能会揭示导航蛋白功能的新见解。重要的是，需要进一步的生化研究来确定导航蛋白AAA +结构域的活性，并研究不同导航蛋白及其结合伙伴之间的潜在相互作用。
