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PreprintCited by 0Phytase and its ApplicationsCalcium signaling and nucleotide metabolismProtein Kinase Regulation and GTPase Signaling

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A small signaling domain controls PPIP5K phosphatase activity in phosphate homeostasis

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Raia, Pierre, Lee, Kitaik, Bartsch, Simon M., Rico-Resendiz, Felix, Portugal-Calisto, Daniela, Vadas, Oscar, Panse, Vikram Govind, Fiedler, Dorothea, Hothorn, Michael·2024·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2024.09.12.612650

Preprint — published as 10.1038/s41467-025-56937-0 · Paper page

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Abstract

Inositol pyrophosphates (PP-InsPs) are highly phosphorylated nutrient messengers. The final step of their biosynthesis is catalyzed by diphosphoinositol pentakisphosphate kinase (PPIP5K) enzymes, which are conserved among fungi, plants, and animals. PPIP5Ks contain an N-terminal kinase domain that generates the active messenger 1,5-InsP 8 and a C-terminal phosphatase domain that participates in PP-InsP catabolism. The balance between kinase and phosphatase activities controls the cellular levels and signaling capacity of 1,5-InsP 8 . Here, we present crystal structures of the apo and substrate-bound Vip1 phosphatase domain from S. cerevisiae (ScVip1 PD ). ScVip1 PD is a phytase-like inositol 1-pyrophosphate phosphatase with two conserved histidine phosphatase catalytic motifs. The enzyme has a strong preference for 1,5-InsP 8 and is inhibited by inorganic phosphate. ScVip1 PD has an α-helical insertion domain stabilized by a structural Zn 2+ binding site, and a unique GAF signaling domain that exists in an open and closed state, allowing channeling of the 1,5-InsP 8 substrate to the active site. Mutations that alter the active site, that restrict the movement of the GAF domain or that modify the charge of the substrate channel, significantly inhibit the activity of the yeast enzyme in vitro , and the function of the Arabidopsis PPIP5K VIH2 in planta . Structural analyses of full-length PPIP5Ks suggest that the kinase and phosphatase are independent enzymatic modules. Taken together, our work reveals the structure, enzymatic mechanism and regulation of eukaryotic PPIP5K phosphatases.

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References 102

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  1. 2018, Intimate connections: Inositol pyrophosphates at the interface of metabolic regulation and cell signaling, Journal Cellular Physiology, 233, 1897, 10.1002/jcp.26017 · DOI
  2. 2024, IP8: A quantitatively minor inositol pyrophosphate signaling molecule that punches above its weight, Advances in Biological Regulation, 91, 101002, 10.1016/j.jbior.2023.101002 · DOI
  3. 10.1016/j.cbpa.2022.102177 · DOI
  4. 10.1126/science.aad9858 · DOI
  5. 10.7554/eLife.87956 · DOI
  6. 10.1038/s41467-023-36466-4 · DOI
  7. 10.1111/mmi.13766 · DOI
  8. 10.1105/tpc.16.00351 · DOI
  9. 10.1073/pnas.0504172102 · DOI
  10. 2019, Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis, eLife, 8, e43582, 10.7554/eLife.43582 · DOI
  11. 10.1016/j.molp.2019.08.002 · DOI
  12. 2021, Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis, Nature Communications, 12, 384, 10.1038/s41467-020-20681-4 · DOI
  13. 10.1016/j.molp.2021.07.011 · DOI
  14. 2021, Mechanism of phosphate sensing and signaling revealed by rice SPX1-PHR2 complex structure, Nat Commun, 12, 7040, 10.1038/s41467-021-27391-5 · DOI
  15. 10.1038/s41467-022-29275-8 · DOI
  16. 10.1074/jbc.M116.765743 · DOI
  17. 10.1073/pnas.1908830117 · DOI
  18. 10.1039/d0sc02144j · DOI
  19. 2024, Homeostatic coordination of cellular phosphate uptake and efflux requires an organelle-based receptor for the inositol pyrophosphate IP8, Cell Rep, 43, 114316, 10.1016/j.celrep.2024.114316 · DOI
  20. 10.1016/S0960-9822(00)80055-X · DOI · Paper page
  21. 10.1074/jbc.M202206200 · DOI
  22. 10.1021/acschembio.9b00423 · DOI
  23. 10.1074/jbc.M704656200 · DOI
  24. 10.1126/science.1139099 · DOI
  25. 10.1073/pnas.1908875117 · DOI
  26. 10.1042/BJ20101437 · DOI
  27. 10.1038/nphys2223 · DOI
  28. 10.1042/BSR20120115 · DOI
  29. 10.1042/BSR20171549 · DOI
  30. 2022, The inositol pyrophosphate metabolism of Dictyostelium discoideum does not regulate inorganic polyphosphate (polyP) synthesis, Advances in Biological Regulation, 83, 100835, 10.1016/j.jbior.2021.100835 · DOI
  31. 10.1111/tpj.12669 · DOI
  32. 10.1105/tpc.114.135160 · DOI
  33. 2021, Wheat inositol pyrophosphate kinase TaVIH2-3B modulates cell-wall composition and drought tolerance in Arabidopsis, BMC Biol, 19, 261, 10.1186/s12915-021-01198-8 · DOI
  34. 10.1101/2024.04.30.591831 · DOI
  35. 10.1128/MCB.00047-18 · DOI
  36. 10.1073/pnas.1702370114 · DOI
  37. 2018, Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse, PLoS Genet, 14, e1007297, 10.1371/journal.pgen.1007297 · DOI
  38. 10.1073/pnas.2020187118 · DOI
  39. 10.1007/s00299-021-02812-3 · DOI
  40. 2022, Activities and Structure-Function Analysis of Fission Yeast Inositol Pyrophosphate (IPP) Kinase-Pyrophosphatase Asp1 and Its Impact on Regulation of pho1 Gene Expression, mBio, 13, e01034
  41. 10.1371/journal.pgen.1004586 · DOI
  42. 10.1021/acs.biochem.5b00532 · DOI
  43. 10.1371/journal.pone.0165286 · DOI
  44. 2020, Analysis of inositol phosphate metabolism by capillary electrophoresis electrospray ionization mass spectrometry, Nat Commun, 11, 6035, 10.1038/s41467-020-19928-x · DOI
  45. 10.1016/j.chembiol.2014.03.009 · DOI
  46. 2022, Structures of Fission Yeast Inositol Pyrophosphate Kinase Asp1 in Ligand-Free, Substrate-Bound, and Product-Bound States, mBio, 13, e03087
  47. 10.1042/BJ20071097 · DOI
  48. 10.1016/j.febslet.2012.06.006 · DOI
  49. 10.1093/nar/gkq366 · DOI · Paper page
  50. 10.1016/S0968-0004(97)01148-1 · DOI
  51. 10.1016/S0960-9822(06)00352-6 · DOI
  52. 10.1093/emboj/19.20.5288 · DOI
  53. 10.1146/annurev-micro-121809-151631 · DOI
  54. 10.1042/bj20031229 · DOI
  55. 2015, Autoinhibition of Bruton’s tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate, Elife, 4, e06074, 10.7554/eLife.06074 · DOI
  56. 10.1038/72371 · DOI
  57. 1992, Overexpression, site-directed mutagenesis, and mechanism of Escherichia coli acid phosphatase, J Biol Chem, 267, 22830, 10.1016/S0021-9258(18)50022-3 · DOI
  58. 1993, Asp304 of Escherichia coli acid phosphatase is involved in leaving group protonation, J Biol Chem, 268, 20778, 10.1016/S0021-9258(19)36851-6 · DOI
  59. 10.1074/jbc.M312202200 · DOI
  60. 2022, Insights to the Structural Basis for the Stereospecificity of the Escherichia coli Phytase, AppA. IJMS, 23, 6346, 10.3390/ijms23116346 · DOI
  61. 2014, A Bacterial Homolog of a Eukaryotic Inositol Phosphate Signaling Enzyme Mediates Cross-kingdom Dialog in the Mammalian Gut, Cell Reports, 6, 646, 10.1016/j.celrep.2014.01.021 · DOI
  62. 10.1016/j.molcel.2004.09.035 · DOI
  63. 10.1534/g3.120.401570 · DOI
  64. 10.1091/mbc.8.12.2677 · DOI
  65. 10.1091/mbc.E16-07-0552 · DOI
  66. 2019, Dynamics of Substrate Processing by PPIP5K2, a Versatile Catalytic Machine, Structure, 27, 1022, 10.1016/j.str.2019.03.007 · DOI
  67. 2023, Activities, substrate specificity, and genetic interactions of fission yeast Siw14, a cysteinyl-phosphatase-type inositol pyrophosphatase, mBio, 14, e02056
  68. 2024, Activities and genetic interactions of fission yeast Aps1, a Nudix-type inositol pyrophosphatase and inorganic polyphosphatase, mBio, 15, e0108424, 10.1128/mbio.01084-24 · DOI
  69. 10.1093/nar/gkaa776 · DOI
  70. 10.1074/jbc.RA117.001670 · DOI
  71. 10.1074/jbc.M209105200 · DOI
  72. 10.1016/j.cellsig.2016.02.002 · DOI
  73. 10.1038/nchembio.667 · DOI
  74. 10.1186/1472-6750-10-50 · DOI
  75. 10.1023/B:JSFG.0000029237.70316.52 · DOI
  76. 10.1107/S0021889809042022 · DOI
  77. 10.1107/S0021889893005588 · DOI
  78. 10.1107/S0021889807021206 · DOI · Paper page
  79. 10.1107/S0907444904019158 · DOI · Paper page
  80. 10.1107/S0907444912001308 · DOI · Paper page
  81. 10.1107/S0907444910051371 · DOI
  82. 10.1016/S0076-6879(03)74002-6 · DOI
  83. 10.1107/S1399004714014795 · DOI
  84. 10.1038/23641 · DOI
  85. 10.1107/S0907444907016605 · DOI
  86. 10.1093/nar/gkm216 · DOI
  87. 10.1002/jcc.20084 · DOI
  88. 10.1039/c9sc00151d · DOI
  89. 10.1016/0076-6879(66)08014-5 · DOI
  90. 10.1016/0003-2697(88)90484-8 · DOI
  91. 10.1002/(SICI)1097-0061(199807)14:10<953::AID-YEA293>3.0.CO;2-U · DOI
  92. 10.1371/journal.pone.0088218 · DOI · Paper page
  93. 10.1046/j.1365-313x.1998.00343.x · DOI
  94. 10.1038/nmeth.2019 · DOI · Paper page
  95. 10.1038/nmeth.4169 · DOI · Paper page
  96. 10.1016/j.molcel.2018.06.042 · DOI
  97. 2021, Dissecting the activation of insulin degrading enzyme by inositol pyrophosphates and their bisphosphonate analogs, Chem Sci, 12, 10696, 10.1039/D1SC02975D · DOI
  98. 10.1093/NAR/GKAB1038 · DOI · Paper page
  99. 10.1021/bi0265067 · DOI
  100. 10.1111/j.1365-2443.2005.00817.x · DOI
  101. 10.1093/nar/gki370 · DOI
  102. 10.2307/2281208 · DOI

Metadata

Authors
Raia, P., Lee, K., Bartsch, S. M., Rico-Resendiz, F., Portugal-Calisto, D., Vadas, O., Panse, V. G., Fiedler, D., & Hothorn, M.
Affiliations
  • University of Geneva (CH)
  • Humboldt-Universität zu Berlin (DE)
  • University of Zurich (CH)
Corresponding author
Hothorn, Michael
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2024-09-12
DOI
10.1101/2024.09.12.612650
OpenAlex
W4402525425
Cited by
0
References
102
Type
posted content
Language
en
Open access
Licence
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Topics
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytase and its Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
inositol pyrophosphates, phosphatase domain, VIP1, phosphate homeostasis, kinase-phosphatase balance, substrate channeling, zinc binding site, Arabidopsis, Saccharomyces cerevisiae, crystal structure, enzyme mechanism

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