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Mechanism of substrate specificity of phosphatidylinositol phosphate kinases.

Muftuoglu Y, Xue Y, Gao X, Wu D, Ha Y
Proc Natl Acad Sci U S A 113 8711-6 (2016)
Related entries: 5e3s, 5e3t

Cited: 16 times
EuropePMC logo PMID: 27439870

Abstract

The phosphatidylinositol phosphate kinase (PIPK) family of enzymes is primarily responsible for converting singly phosphorylated phosphatidylinositol derivatives to phosphatidylinositol bisphosphates. As such, these kinases are central to many signaling and membrane trafficking processes in the eukaryotic cell. The three types of phosphatidylinositol phosphate kinases are homologous in sequence but differ in catalytic activities and biological functions. Type I and type II kinases generate phosphatidylinositol 4,5-bisphosphate from phosphatidylinositol 4-phosphate and phosphatidylinositol 5-phosphate, respectively, whereas the type III kinase produces phosphatidylinositol 3,5-bisphosphate from phosphatidylinositol 3-phosphate. Based on crystallographic analysis of the zebrafish type I kinase PIP5Kα, we identified a structural motif unique to the kinase family that serves to recognize the monophosphate on the substrate. Our data indicate that the complex pattern of substrate recognition and phosphorylation results from the interplay between the monophosphate binding site and the specificity loop: the specificity loop functions to recognize different orientations of the inositol ring, whereas residues flanking the phosphate binding Arg244 determine whether phosphatidylinositol 3-phosphate is exclusively bound and phosphorylated at the 5-position. This work provides a thorough picture of how PIPKs achieve their exquisite substrate specificity.

Articles - 5e3u mentioned but not cited (2)

  1. Mechanism of substrate specificity of phosphatidylinositol phosphate kinases. Muftuoglu Y, Xue Y, Gao X, Wu D, Ha Y. Proc Natl Acad Sci U S A 113 8711-8716 (2016)
  2. Structural insights into lethal contractural syndrome type 3 (LCCS3) caused by a missense mutation of PIP5Kγ. Zeng X, Uyar A, Sui D, Donyapour N, Wu D, Dickson A, Hu J. Biochem J 475 2257-2269 (2018)


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  1. Lipid composition of the cancer cell membrane. Szlasa W, Zendran I, Zalesińska A, Tarek M, Kulbacka J. J Bioenerg Biomembr 52 321-342 (2020)
  2. Expanding role of PI5P4Ks in cancer: A promising druggable target. Arora GK, Palamiuc L, Emerling BM. FEBS Lett 596 3-16 (2022)
  3. Insights into Membrane Curvature Sensing and Membrane Remodeling by Intrinsically Disordered Proteins and Protein Regions. Has C, Sivadas P, Das SL. J Membr Biol 255 237-259 (2022)
  4. A regulatory role of membrane by direct modulation of the catalytic kinase domain. Prakash P. Small GTPases 12 246-256 (2021)
  5. Extracellular ATP and Macropinocytosis: Their Interactive and Mutually Supportive Roles in Cell Growth, Drug Resistance, and EMT in Cancer. Evers M, Song J, Chen X. Subcell Biochem 98 61-83 (2022)

Articles citing this publication (9)

  1. PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism. Wang DG, Paddock MN, Lundquist MR, Sun JY, Mashadova O, Amadiume S, Bumpus TW, Hodakoski C, Hopkins BD, Fine M, Hill A, Yang TJ, Baskin JM, Dow LE, Cantley LC. Cell Rep 27 1991-2001.e5 (2019)
  2. Membrane Recognition and Binding by the Phosphatidylinositol Phosphate Kinase PIP5K1A: A Multiscale Simulation Study. Amos STA, Kalli AC, Shi J, Sansom MSP. Structure 27 1336-1346.e2 (2019)
  3. Plasma membrane processes are differentially regulated by type I phosphatidylinositol phosphate 5-kinases and RASSF4. de la Cruz L, Traynor-Kaplan A, Vivas O, Hille B, Jensen JB. J Cell Sci 133 jcs233254 (2020)
  4. Structural basis of membrane recognition of Toxoplasma gondii vacuole by Irgb6. Saijo-Hamano Y, Sherif AA, Pradipta A, Sasai M, Sakai N, Sakihama Y, Yamamoto M, Standley DM, Nitta R. Life Sci Alliance 5 e202101149 (2022)
  5. Membrane-mediated dimerization potentiates PIP5K lipid kinase activity. Hansen SD, Lee AA, Duewell BR, Groves JT. Elife 11 e73747 (2022)
  6. The GTP responsiveness of PI5P4Kβ evolved from a compromised trade-off between activity and specificity. Takeuchi K, Ikeda Y, Senda M, Harada A, Okuwaki K, Fukuzawa K, Nakagawa S, Yu HY, Nagase L, Imai M, Sasaki M, Lo YH, Ito D, Osaka N, Fujii Y, Sasaki AT, Senda T. Structure 30 886-899.e4 (2022)
  7. Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases. Sun M, Zhang C, Sui D, Yang C, Pyeon D, Huang X, Hu J. Chemistry 29 e202202083 (2023)
  8. Identification and Analysis of the Expression of the PIP5K Gene Family in Tomatoes. Wang Z, Wang Z, Li X, Chen Z, Liu Y, Zhang F, Dai Q, Yu Q, Li N. Int J Mol Sci 25 159 (2023)
  9. The Silencing of GhPIP5K2 and GhPIP5K22 Weakens Abiotic Stress Tolerance in Upland Cotton (Gossypium hirsutum). Ling P, Ju J, Zhang X, Wei W, Luo J, Li Y, Hai H, Shang B, Cheng H, Wang C, Zhang X, Su J. Int J Mol Sci 25 1511 (2024)


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