南方科技大学刘忠民等研究人员合作揭示人类钙泵SPCA1的结构和运输机制。相关论文于2023年5月31日在线发表在《细胞研究》杂志上。

研究人员确定了人类分泌途径的Ca²⁺-ATP酶1（hSPCA1）在一系列中间状态下的六个冷冻电镜（cryo-EM）结构，揭示了一个几乎完整的构象循环。在分子动力学模拟的帮助下，这些结构为hSPCA1的Ca²⁺进入和释放提供了明确的结构基础。与其他研究良好的P型II ATP酶相比，研究人员发现hSPCA1在ATP结合和磷酸化过程中经历了独特的构象变化。此外，研究人员观察到由跨膜螺旋4L和6的分离引起的Ca²⁺结合位点的构象变形，并揭示了一种独特的Ca²⁺释放机制。具体而言，研究人员确定了一个长期寻找的P型IIA ATP酶的CaE2P状态的结构，并为Ca²⁺运输循环提供了宝贵的见解。

总之，这些发现增强了人们对hSPCA1运输Ca²⁺的理解，并扩大了人们对P型ATP酶的认识。

据介绍，SPCA在维持Ca²⁺平衡方面起着关键作用，但SPCA介导的Ca²⁺运输的确切机制仍不清楚。

附：英文原文

Title: Structure and transport mechanism of the human calcium pump SPCA1

Author: Wu, Mengqi, Wu, Cang, Song, Tiefeng, Pan, Kewu, Wang, Yong, Liu, Zhongmin

Issue&Volume: 2023-05-31

Abstract: Secretory-pathway Ca2+-ATPases (SPCAs) play critical roles in maintaining Ca2+ homeostasis, but the exact mechanism of SPCAs-mediated Ca2+ transport remains unclear. Here, we determined six cryo-electron microscopy (cryo-EM) structures of human SPCA1 (hSPCA1) in a series of intermediate states, revealing a near-complete conformational cycle. With the aid of molecular dynamics simulations, these structures offer a clear structural basis for Ca2+ entry and release in hSPCA1. We found that hSPCA1 undergoes unique conformational changes during ATP binding and phosphorylation compared to other well-studied P-type II ATPases. In addition, we observed a conformational distortion of the Ca2+-binding site induced by the separation of transmembrane helices 4L and 6, unveiling a distinct Ca2+ release mechanism. Particularly, we determined a structure of the long-sought CaE2P state of P-type IIA ATPases, providing valuable insights into the Ca2+ transport cycle. Together, these findings enhance our understanding of Ca2+ transport by hSPCA1 and broaden our knowledge of P-type ATPases.

DOI: 10.1038/s41422-023-00827-x

Source: https://www.nature.com/articles/s41422-023-00827-x