A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

Article Article scientifique Article A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis eng 2025-02-19 author Raia Pierre 0000-0003-3469-1922 930734 Département des sciences végétales (BIVEG) author Lee Kitaik 0000-0002-7761-5586 926549 author Bartsch Simon M. 0000-0002-2215-7901 author Rico Resendiz Félix Edgardo 962981 Département des sciences végétales (BIVEG) author Portugal-Calisto Daniela author Vadas Oscar 0000-0003-3511-6479 508966 Services communs de la faculté de médecine (SCMU) author Panse Vikram Govind 0000-0002-4770-7068 author Fiedler Dorothea 0000-0002-0798-946X author Hothorn Michael 0000-0002-3597-5698 826130 Département des sciences végétales (BIVEG) 1753 10.1038/s41467-025-56937-0 39966396 2041-1723 PMC11836120 https://www.nature.com/articles/s41467-025-56937-0 Inositol pyrophosphates (PP-InsPs) are eukaryotic nutrient messengers. The N-terminal kinase domain of diphosphoinositol pentakisphosphate kinase (PPIP5K) generates the messenger 1,5-InsP 8 , the C-terminal phosphatase domain catalyzes PP-InsP breakdown. The balance between kinase and phosphatase activities regulates 1,5-InsP 8 levels. Here, we present crystal structures of the apo and substrate-bound PPIP5K phosphatase domain from S. cerevisiae (ScVip1 PD ). ScVip1 PD is a phytase-like inositol 1-pyrophosphate histidine phosphatase with two conserved catalytic motifs. The enzyme has a strong preference for 1,5-InsP 8 and is inhibited by inorganic phosphate. It contains an α-helical insertion domain stabilized by a structural Zn 2+ binding site, and a unique GAF domain that channels the substrate to the active site. Mutations that alter the active site, restrict the movement of the GAF domain, or change the substrate channel’s charge inhibit the enzyme activity in vitro, and Arabidopsis VIH2 in planta . Our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases. Enzyme mechanisms X-ray crystallography Plant signalling Homeostasis Permeation and transport Arabidopsis Proteins / chemistry Arabidopsis Proteins / genetics Arabidopsis Proteins / metabolism Arabidopsis / enzymology Arabidopsis / genetics Arabidopsis / metabolism Catalytic Domain Crystallography, X-Ray Inositol Phosphates / metabolism Models, Molecular Mutation Phosphates / chemistry Phosphates / metabolism Phosphoric Monoester Hydrolases / chemistry Phosphoric Monoester Hydrolases / genetics Phosphoric Monoester Hydrolases / metabolism Phosphotransferases (Phosphate Group Acceptor) / chemistry Phosphotransferases (Phosphate Group Acceptor) / genetics Phosphotransferases (Phosphate Group Acceptor) / metabolism Protein Domains Saccharomyces cerevisiae Proteins / chemistry Saccharomyces cerevisiae Proteins / genetics Saccharomyces cerevisiae Proteins / metabolism Saccharomyces cerevisiae / enzymology Saccharomyces cerevisiae / genetics Saccharomyces cerevisiae / metabolism Signal Transduction Substrate Specificity Zinc / metabolism Dewey 610 Dewey 580 Howard Hughes Medical Institute 55008733 Swiss National Science Foundation Illuminating the functions, cellular locations and regulation of inositol pyrophosphate nutrient messengers 209412 CH Programmes 45 Département des sciences végétales 163 3 Faculté de médecine 2 false 830 Groupe Hothorn https://www.wwpdb.org/pdb?id=pdb_00009gr8 https://www.wwpdb.org/pdb?id=pdb_00009grh https://www.wwpdb.org/pdb?id=pdb_00009grn https://www.wwpdb.org/pdb?id=pdb_00009gro https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD056020 Nature communications 16 1 65ac7510-b495-4307-877c-32d2478447a3 Article (Published version) Public Article_scientifique_from_crossref.pdf 7522781 application/pdf CC BY-4.0 807ebf063a92140045a11f71b51913e8158233eb690b85bb968b94408fbeacaa e679b981-66c8-4de1-b4f6-bb52a227ae13 Appendix Public 41467_2025_56937_MOESM1_ESM.pdf 10913169 application/pdf Suppl. info 82c07d8647ec952b49a0a47ef01a82b938b201524c0d66c93b11c7610424e4cc 04b07e07-1e79-484c-bbc1-59f1b3c5b59a Appendix Public 41467_2025_56937_MOESM2_ESM.pdf 262893 application/pdf Reporting summary ef31fbe37725f2a16d8c1f556e749c7506902b8fbf9db69afd940a6bb7125ff3 726c4f39-58db-4c6c-bb64-b524d732ae46 Supplemental data Public 41467_2025_56937_MOESM4_ESM.zip 3109780 application/zip Source data 1c964390ac845d057484e9067e13d16f5e7d285bf11cfc96ddee853421b7243d openAccess Faculté des sciences / Section de biologie / Département des sciences végétales Faculté de médecine

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A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis	Nature communications			2025	62	27

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