Howard Hughes Medical Institute, Department of Cardiology, Boston Children's Hospital, 320 Longwood Avenue, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA.
Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
Cell. 2014 May 8;157(4):808-22. doi: 10.1016/j.cell.2014.02.056.
Spermatozoa must leave one organism, navigate long distances, and deliver their paternal DNA into a mature egg. For successful navigation and delivery, a sperm-specific calcium channel is activated in the mammalian flagellum. The genes encoding this channel (CatSpers) appear first in ancient uniflagellates, suggesting that sperm use adaptive strategies developed long ago for single-cell navigation. Here, using genetics, super-resolution fluorescence microscopy, and phosphoproteomics, we investigate the CatSper-dependent mechanisms underlying this flagellar switch. We find that the CatSper channel is required for four linear calcium domains that organize signaling proteins along the flagella. This unique structure focuses tyrosine phosphorylation in time and space as sperm acquire the capacity to fertilize. In heterogeneous sperm populations, we find unique molecular phenotypes, but only sperm with intact CatSper domains that organize time-dependent and spatially specific protein tyrosine phosphorylation successfully migrate. These findings illuminate flagellar adaptation, signal transduction cascade organization, and fertility.
精子必须离开一个生物体，在体内导航很长的距离，并将其父系 DNA 输送到成熟的卵子中。为了成功地导航和输送，哺乳动物鞭毛中的一个精子特异性钙通道被激活。编码这个通道的基因（CatSper）首先出现在古老的单细胞生物中，这表明精子使用了很久以前为单细胞导航开发的适应性策略。在这里，我们使用遗传学、超分辨率荧光显微镜和磷酸化蛋白质组学来研究这种鞭毛开关背后的 CatSper 依赖性机制。我们发现，CatSper 通道对于组织沿着鞭毛排列的信号蛋白的四个线性钙域是必需的。这种独特的结构将酪氨酸磷酸化集中在时间和空间上，因为精子获得了受精的能力。在异质的精子群体中，我们发现了独特的分子表型，但只有具有完整 CatSper 结构域的精子能够成功地迁移，该结构域可以组织时间依赖性和空间特异性的蛋白质酪氨酸磷酸化。这些发现阐明了鞭毛的适应性、信号转导级联的组织以及生育能力。
