Structural basis for the substrate recognition mechanism of ATP-sulfurylase domain of human PAPS synthase 2
Autor: | Zhaoyuan Hou, Hai Gao, Liang Zhang, Pan Zhang, Houwen Lin, Lin Zhang |
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Rok vydání: | 2022 |
Předmět: |
Models
Molecular Protein Conformation alpha-Helical Genetic Vectors Phosphoadenosine Phosphosulfate Biophysics Gene Expression Phenylalanine Crystallography X-Ray Biochemistry Substrate Specificity chemistry.chemical_compound Adenosine Triphosphate Sulfation Multienzyme Complexes Catalytic Domain Escherichia coli Humans Protein Interaction Domains and Motifs Amino Acid Sequence Cloning Molecular Molecular Biology chemistry.chemical_classification Sequence Homology Amino Acid ATP synthase biology Drug discovery Substrate (chemistry) Cell Biology Recombinant Proteins Sulfate Adenylyltransferase Neoplasm Proteins 3'-Phosphoadenosine-5'-phosphosulfate Enzyme chemistry biology.protein Thermodynamics Protein Conformation beta-Strand Sequence Alignment Function (biology) Protein Binding |
Zdroj: | Biochemical and Biophysical Research Communications. 586:1-7 |
ISSN: | 0006-291X |
Popis: | Sulfation is an essential modification on biomolecules in living cells, and 3'-Phosphoadenosine-5'-phosphosulfate (PAPS) is its unique and universal sulfate donor. Human PAPS synthases (PAPSS1 and 2) are the only enzymes that catalyze PAPS production from inorganic sulfate. Unexpectedly, PAPSS1 and PAPSS2 do not functional complement with each other, and abnormal function of PAPSS2 but not PAPSS1 leads to numerous human diseases including bone development diseases, hormone disorder and cancers. Here, we reported the crystal structures of ATP-sulfurylase domain of human PAPSS2 (ATPS2) and ATPS2 in complex with is product 5'-phosphosulfate (APS). We demonstrated that ATPS2 recognizes the substrates by using family conserved residues located on the HXXH and PP motifs, and achieves substrate binding and releasing by employing a non-conserved phenylalanine (Phe550) through a never observed flipping mechanism. Our discovery provides additional information to better understand the biological function of PAPSS2 especially in tumorigenesis, and may facilitate the drug discovery against this enzyme. |
Databáze: | OpenAIRE |
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