7YIV

The Crystal Structure of Human Tissue Nonspecific Alkaline Phosphatase (ALPL) at Basic pH

7YIV の概要

• エントリーDOI: 10.2210/pdb7yiv/pdb
• 分子名称: Alkaline phosphatase, tissue-nonspecific isozyme, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• 機能のキーワード: alkaline phosphatase, bone mineralization, catalytic network, hypophosphatasia, structural biology, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 468052.86

構造登録者

Cao, Y.,Qin, A.,Yu, Y.T.,Yao, D.Q.,Zhang, Q.,Rao, B.,Xia, Y.,Lu, Y. (登録日: 2022-07-18, 公開日: 2023-07-19, 最終更新日: 2024-11-20)

主引用文献

Yu, Y.,Rong, K.,Yao, D.,Zhang, Q.,Cao, X.,Rao, B.,Xia, Y.,Lu, Y.,Shen, Y.,Yao, Y.,Xu, H.,Ma, P.,Cao, Y.,Qin, A.
The structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase.
Nat Commun, 14:4048-4048, 2023

PubMed 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.

PubMed: 37422472
DOI: 10.1038/s41467-023-39833-3

実験手法

X-RAY DIFFRACTION (3.18 Å)