7fh3
From Proteopedia
Crystal structure of the ATP sulfurylase domain of human PAPSS2
Structural highlights
DiseasePAPS2_HUMAN Defects in PAPSS2 are the cause of spondyloepimetaphyseal dysplasia Pakistani type (SEMD-PA) [MIM:612847. A bone disease characterized by epiphyseal dysplasia with mild metaphyseal abnormalities. Clinical features include short stature evidenced at birth, short and bowed lower limbs, mild brachydactyly, kyphoscoliosis, abnormal gait, enlarged knee joints. Some patients may manifest premature pubarche and hyperandrogenism associated with skeletal dysplasia and short stature.[1] [2] FunctionPAPS2_HUMAN Bifunctional enzyme with both ATP sulfurylase and APS kinase activity, which mediates two steps in the sulfate activation pathway. The first step is the transfer of a sulfate group to ATP to yield adenosine 5'-phosphosulfate (APS), and the second step is the transfer of a phosphate group from ATP to APS yielding 3'-phosphoadenylylsulfate (PAPS: activated sulfate donor used by sulfotransferase). In mammals, PAPS is the sole source of sulfate; APS appears to be only an intermediate in the sulfate-activation pathway. May have a important role in skeletogenesis during postnatal growth (By similarity). Publication Abstract from PubMedSulfation 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. Structural basis for the substrate recognition mechanism of ATP-sulfurylase domain of human PAPS synthase 2.,Zhang P, Zhang L, Hou Z, Lin H, Gao H, Zhang L Biochem Biophys Res Commun. 2022 Jan 1;586:1-7. doi: 10.1016/j.bbrc.2021.11.062. , Epub 2021 Nov 19. PMID:34818583[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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