Nature Communications ( IF 14.7 ) Pub Date : 2023-07-08 , DOI: 10.1038/s41467-023-39833-3
Yating Yu 1, 2 , Kewei Rong 1 , Deqiang Yao 3 , Qing Zhang 1, 2 , Xiankun Cao 1 , Bing Rao 1, 2 , Ying Xia 2 , Yi Lu 2 , Yafeng Shen 2 , Ying Yao 4 , Hongtao Xu 4 , Peixiang Ma 1 , Yu Cao 1, 2 , An Qin 1
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Hypophosphatasia (HPP) is a metabolic bone disease that manifests as developmental abnormalities in bone and dental tissues. HPP patients exhibit hypo-mineralization and osteopenia due to the deficiency or malfunction of tissue non-specific alkaline phosphatase (TNAP), which catalyzes the hydrolysis of phosphate-containing molecules outside the cells, promoting the deposition of hydroxyapatite in the extracellular matrix. Despite the identification of hundreds of pathogenic TNAP mutations, the detailed molecular pathology of HPP remains unclear. Here, to address this issue, we determine the crystal structures of human TNAP at near-atomic resolution and map the major pathogenic mutations onto the structure. Our study reveals an unexpected octameric architecture for TNAP, which is generated by the tetramerization of dimeric TNAPs, potentially stabilizing the TNAPs in the extracellular environments. Moreover, we use cryo-electron microscopy to demonstrate that the TNAP agonist antibody (JTALP001) forms a stable complex with TNAP by binding to the octameric interface. The administration of JTALP001 enhances osteoblast mineralization and promoted recombinant TNAP-rescued mineralization in TNAP knockout osteoblasts. Our findings elucidate the structural pathology of HPP and highlight the therapeutic potential of the TNAP agonist antibody for osteoblast-associated bone disorders.
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组织非特异性碱性磷酸酶功能障碍引起的低磷酸酯酶症的结构病理学
低磷酸酯酶症(HPP)是一种代谢性骨病,表现为骨和牙齿组织发育异常。HPP患者由于组织非特异性碱性磷酸酶(TNAP)缺乏或功能障碍而表现出矿化低下和骨质减少,TNAP催化细胞外含磷酸盐分子的水解,促进羟基磷灰石在细胞外基质中的沉积。尽管已鉴定出数百种致病性 TNAP 突变,但 HPP 的详细分子病理学仍不清楚。在这里,为了解决这个问题,我们以近原子分辨率确定了人类 TNAP 的晶体结构,并将主要致病突变映射到该结构上。我们的研究揭示了一种意想不到的 TNAP 八聚体结构,它是由二聚 TNAP 四聚化产生的,有可能稳定细胞外环境中的 TNAP。此外,我们使用冷冻电子显微镜证明 TNAP 激动剂抗体 (JTALP001) 通过与八聚体界面结合,与 TNAP 形成稳定的复合物。JTALP001 的施用增强了成骨细胞矿化,并促进了 TNAP 敲除成骨细胞中重组 TNAP 拯救的矿化。我们的研究结果阐明了 HPP 的结构病理学,并强调了 TNAP 激动剂抗体对成骨细胞相关骨疾病的治疗潜力。