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TitleThe structural pathology for hypophosphatasia caused by malfunctional tissue non-specific alkaline phosphatase.
Journal, issue, pagesNat Commun, Vol. 14, Issue 1, Page 4048, Year 2023
Publish dateJul 8, 2023
AuthorsYating 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 / An Qin /
PubMed AbstractHypophosphatasia (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 ...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.
External linksNat Commun / PubMed:37422472 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.89 - 3.18 Å
Structure data

33865

7yix

EMDB-33865, PDB-7yix:
The Cryo-EM Structure of Human Tissue Nonspecific Alkaline Phosphatase and Single-Chain Fragment Variable (ScFv) Complex.
Method: EM (single particle) / Resolution: 2.96 Å

PDB-7yiv:
The Crystal Structure of Human Tissue Nonspecific Alkaline Phosphatase (ALPL) at Basic pH
Method: X-RAY DIFFRACTION / Resolution: 3.18 Å

PDB-7yiw:
The Crystal Structure of Human Tissue Nonspecific Alkaline Phosphatase (ALPL) at Acidic pH
Method: X-RAY DIFFRACTION / Resolution: 2.89 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsHYDROLASE / alkaline phosphatase / bone mineralization / catalytic network / hypophosphatasia / structural biology

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