Structural basis for the substrate recognition mechanism of ATP-sulfurylase domain of human PAPS synthase 2

Pan Zhang; Lin Zhang; Zhaoyuan Hou; Houwen Lin; Hai Gao; Liang Zhang

doi:10.1016/j.bbrc.2021.11.062

Structural basis for the substrate recognition mechanism of ATP-sulfurylase domain of human PAPS synthase 2

Biochem Biophys Res Commun. 2022 Jan 1:586:1-7. doi: 10.1016/j.bbrc.2021.11.062. Epub 2021 Nov 19.

Authors

Pan Zhang¹, Lin Zhang², Zhaoyuan Hou³, Houwen Lin⁴, Hai Gao⁵, Liang Zhang⁶

Affiliations

¹ Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
² Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: zhanglin777@sjtu.edu.cn.
³ Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Department of Biochemistry & Molecular Cellular Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴ Research Centre for Marine Drugs, State Key Laboratory of Oncogene and Related Genes, Department of Pharmacy, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
⁵ Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: gaohai@fudan.edu.cn.
⁶ Department of Pharmacology and Chemical Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. Electronic address: liangzhang2014@sjtu.edu.cn.

PMID: 34818583
DOI: 10.1016/j.bbrc.2021.11.062

Abstract

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.

Keywords: 3′-phosphoadenosine-5′-phosphosulfate; 5′-phosphosulfate; Human PAPS synthase; Sulfation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / chemistry*
Adenosine Triphosphate / metabolism
Amino Acid Sequence
Catalytic Domain
Cloning, Molecular
Crystallography, X-Ray
Escherichia coli / genetics
Escherichia coli / metabolism
Gene Expression
Genetic Vectors / chemistry
Genetic Vectors / metabolism
Humans
Models, Molecular
Multienzyme Complexes / chemistry*
Multienzyme Complexes / genetics
Multienzyme Complexes / metabolism
Neoplasm Proteins / chemistry*
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism
Phosphoadenosine Phosphosulfate / chemistry*
Phosphoadenosine Phosphosulfate / metabolism
Protein Binding
Protein Conformation, alpha-Helical
Protein Conformation, beta-Strand
Protein Interaction Domains and Motifs
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Sequence Alignment
Sequence Homology, Amino Acid
Substrate Specificity
Sulfate Adenylyltransferase / chemistry*
Sulfate Adenylyltransferase / genetics
Sulfate Adenylyltransferase / metabolism
Thermodynamics

Substances

Multienzyme Complexes
Neoplasm Proteins
Recombinant Proteins
Phosphoadenosine Phosphosulfate
Adenosine Triphosphate
PAPS synthetase
Sulfate Adenylyltransferase