Determinants shaping the nanoscale architecture of the mouse rod outer segment.
Determinants shaping the nanoscale architecture of the mouse rod outer segment.
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DOI：
10.7554/elife.72817
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发表时间：
2021-12-21
期刊：
影响因子：
7.7
通讯作者：
Baumeister W
中科院分区：
文献类型：
--
作者：
Pöge M;Mahamid J;Imanishi SS;Plitzko JM;Palczewski K;Baumeister W
视杆细胞外段（ROS）是视杆光感受器细胞特化的感觉纤毛，其独特的膜结构为光转导（视觉的起始步骤）奠定了基础。ROS的结构特征是由一系列形状相同且紧密排列的膜盘组成，膜盘中负载着视觉受体视紫红质。据报道，多种遗传变异会损害ROS的超微结构，从而损害光感受器的活力和功能。然而，导致ROS膜盘排列极其精确的结构基础以及遗传性疾病背后的分子机制仍然不清楚。在此，对天然ROS进行的分子分辨率的冷冻电子断层扫描（cryo - ET）为ROS膜结构的关键结构决定因素提供了见解。我们的数据证实了之前观察到的两种可能有助于ROS膜盘纳米级精确堆叠的分子连接物/间隔物的存在。我们进一步提供证据表明，膜盘边缘的极端曲率半径是由由外周蛋白 - 2（PRPH2）和视杆细胞外段膜蛋白1（ROM1）寡聚体组成的连续超分子组装所决定的。我们认为，这些分子组装共同构成了高度特化的ROS功能结构的结构基础。我们的冷冻电子断层扫描数据为ROS中的分子结构提供了新的定量和结构信息，并证实了之前关于某些导致失明的PRPH2突变病理机制的研究结果。
The unique membrane organization of the rod outer segment (ROS), the specialized sensory cilium of rod photoreceptor cells, provides the foundation for phototransduction, the initial step in vision. ROS architecture is characterized by a stack of identically shaped and tightly packed membrane disks loaded with the visual receptor rhodopsin. A wide range of genetic aberrations have been reported to compromise ROS ultrastructure, impairing photoreceptor viability and function. Yet, the structural basis giving rise to the remarkably precise arrangement of ROS membrane stacks and the molecular mechanisms underlying genetically inherited diseases remain elusive. Here, cryo-electron tomography (cryo-ET) performed on native ROS at molecular resolution provides insights into key structural determinants of ROS membrane architecture. Our data confirm the existence of two previously observed molecular connectors/spacers which likely contribute to the nanometer-scale precise stacking of the ROS disks. We further provide evidence that the extreme radius of curvature at the disk rims is enforced by a continuous supramolecular assembly composed of peripherin-2 (PRPH2) and rod outer segment membrane protein 1 (ROM1) oligomers. We suggest that together these molecular assemblies constitute the structural basis of the highly specialized ROS functional architecture. Our Cryo-ET data provide novel quantitative and structural information on the molecular architecture in ROS and substantiate previous results on proposed mechanisms underlying pathologies of certain PRPH2 mutations leading to blindness.