The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase

Yating Yu, Kewei Rong, Deqiang Yao, Qing Zhang, Xiankun Cao, Bing Rao, Ying Xia, Yi Lu, Yafeng Shen, Ying Yao, Hongtao Xu, Peixiang Ma (), Yu Cao () and An Qin ()
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Yating Yu: Shanghai Jiao Tong University School of Medicine
Kewei Rong: Shanghai Jiao Tong University School of Medicine
Deqiang Yao: Shanghai Jiao Tong University School of Medicine
Qing Zhang: Shanghai Jiao Tong University School of Medicine
Xiankun Cao: Shanghai Jiao Tong University School of Medicine
Bing Rao: Shanghai Jiao Tong University School of Medicine
Ying Xia: Shanghai Jiao Tong University School of Medicine
Yi Lu: Shanghai Jiao Tong University School of Medicine
Yafeng Shen: Shanghai Jiao Tong University School of Medicine
Ying Yao: ShanghaiTech University
Hongtao Xu: ShanghaiTech University
Peixiang Ma: Shanghai Jiao Tong University School of Medicine
Yu Cao: Shanghai Jiao Tong University School of Medicine
An Qin: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39833-3

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