7YIV

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

Summary for 7YIV

• Entry DOI: 10.2210/pdb7yiv/pdb
• Descriptor: 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)
• Functional Keywords: alkaline phosphatase, bone mineralization, catalytic network, hypophosphatasia, structural biology, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 468052.86

Authors

Cao, Y.,Qin, A.,Yu, Y.T.,Yao, D.Q.,Zhang, Q.,Rao, B.,Xia, Y.,Lu, Y. (deposition date: 2022-07-18, release date: 2023-07-19, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (3.18 Å)