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冷冻电镜结构解析揭示人类 SPCA1a 蛋白将 Ca/Mn 转运进入高尔基体的分子机制。

Cryo-EM structures of human SPCA1a reveal the mechanism of Ca/Mn transport into the Golgi apparatus.

机构信息

Institute of Multidisciplinary Research for Advanced Materials, Tohoku University, Sendai, Miyagi 980-8577, Japan.

Department of Molecular and Chemical Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8577, Japan.

出版信息

Sci Adv. 2023 Mar 3;9(9):eadd9742. doi: 10.1126/sciadv.add9742.

DOI:10.1126/sciadv.add9742
PMID:36867705
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9984183/
Abstract

Secretory pathway Ca/Mn ATPase 1 (SPCA1) actively transports cytosolic Ca and Mn into the Golgi lumen, playing a crucial role in cellular calcium and manganese homeostasis. Detrimental mutations of the gene encoding SPCA1 cause Hailey-Hailey disease. Here, using nanobody/megabody technologies, we determined cryo-electron microscopy structures of human SPCA1a in the ATP and Ca/Mn-bound (E1-ATP) state and the metal-free phosphorylated (E2P) state at 3.1- to 3.3-Å resolutions. The structures revealed that Ca and Mn share the same metal ion-binding pocket with similar but notably different coordination geometries in the transmembrane domain, corresponding to the second Ca-binding site in sarco/endoplasmic reticulum Ca-ATPase (SERCA). In the E1-ATP to E2P transition, SPCA1a undergoes similar domain rearrangements to those of SERCA. Meanwhile, SPCA1a shows larger conformational and positional flexibility of the second and sixth transmembrane helices, possibly explaining its wider metal ion specificity. These structural findings illuminate the unique mechanisms of SPCA1a-mediated Ca/Mn transport.

摘要

分泌途径 Ca/Mn ATP 酶 1（SPCA1）主动将细胞质中的 Ca 和 Mn 转运到高尔基体腔中，在细胞内钙和锰的动态平衡中发挥着关键作用。编码 SPCA1 的基因的有害突变会导致 Hailey-Hailey 病。在这里，我们使用纳米体/巨抗体技术，在 3.1-3.3Å 的分辨率下确定了人类 SPCA1a 在 ATP 和 Ca/Mn 结合（E1-ATP）状态以及无金属磷酸化（E2P）状态下的冷冻电子显微镜结构。这些结构表明，Ca 和 Mn 共享相同的金属离子结合口袋，在跨膜域中具有相似但明显不同的配位几何形状，对应于肌浆/内质网 Ca-ATP 酶（SERCA）的第二个 Ca 结合位点。在 E1-ATP 到 E2P 的转变中，SPCA1a 经历了与 SERCA 相似的结构重排。同时，SPCA1a 显示出第二和第六跨膜螺旋更大的构象和位置灵活性，这可能解释了其更广泛的金属离子特异性。这些结构发现阐明了 SPCA1a 介导的 Ca/Mn 转运的独特机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/48657256a9fb/sciadv.add9742-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/975b19664fa0/sciadv.add9742-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/9ca0455e60db/sciadv.add9742-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/0a46898aecc3/sciadv.add9742-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/34bd3e095e5c/sciadv.add9742-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/fdc2c78876ff/sciadv.add9742-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/48657256a9fb/sciadv.add9742-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/975b19664fa0/sciadv.add9742-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/9ca0455e60db/sciadv.add9742-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/0a46898aecc3/sciadv.add9742-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/34bd3e095e5c/sciadv.add9742-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/fdc2c78876ff/sciadv.add9742-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54d5/9984183/48657256a9fb/sciadv.add9742-f6.jpg

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