Home LiteratureArticle Details
PMID: 20559318 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Review

Translation of the phosphoinositide code by PI effectors.

Nature chemical biology ·Vol. 6 ·No. 7 ·2010-07-00 ·Pages 507-13

Kutateladze TG

Abstract

Phosphoinositide (PI) lipids are essential components of eukaryotic cell membranes. They are produced by mono-, bis- and trisphosphorylation of the inositol headgroup of phosphatidylinositol (PtdIns) and are concentrated in separate pools of cytosolic membranes. PIs serve as markers of the cell compartments and form unique docking sites for protein effectors. Collectively, seven known PIs, the protein effectors that bind them and enzymes that generate or modify PIs compose a remarkably complex protein-lipid signaling network. A number of cytosolic proteins contain one or several effector modules capable of recognizing individual PIs and recruiting the host proteins to distinct intracellular compartment. The recently determined atomic-resolution structures and membrane-targeting mechanisms of a dozen PI effectors have provided insights into the molecular basis for regulation of endocytic membrane trafficking and signaling. In this review, I highlight the structural aspects of the deciphering of the 'PI code' by the most common PI-recognizing effectors and discuss the mechanistic details of their membrane anchoring.

MeSH Terms
Gene Expression Regulation Models, Molecular Phosphatidylinositols/genetics,metabolism Protein Structure, Tertiary
Chemicals
Phosphatidylinositols
Authors & Affiliations
1 authors, click to expand affiliations / ORCID
Kutateladze Tatiana G
Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado, USA. tatiana.kutateladze@ucdenver.edu
References (100)
100 references, click to expand
  1. The prevalence and significance of PDZ domain-phosphoinositide interactions.
    Biochim Biophys Acta. 2006 Aug;1761(8):947-56 PMID: 16884951
  2. Structural analysis of the carboxy terminal PH domain of pleckstrin bound to D-myo-inositol 1,2,3,5,6-pentakisphosphate.
    BMC Struct Biol. 2007 Nov 22;7:80 PMID: 18034889
  3. Mutation of the pleckstrin homology domain of Bruton's tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity.
    J Biol Chem. 1996 Nov 29;271(48):30303-6 PMID: 8939985
  4. Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain.
    Cell. 1995 Dec 15;83(6):1037-46 PMID: 8521504
  5. Orientation and penetration depth of monolayer-bound p40phox-PX.
    Biochemistry. 2006 Nov 14;45(45):13566-75 PMID: 17087510
  6. The FYVE domain of early endosome antigen 1 is required for both phosphatidylinositol 3-phosphate and Rab5 binding. Critical role of this dual interaction for endosomal localization.
    J Biol Chem. 2000 Feb 4;275(5):3699-705 PMID: 10652369
  7. Targeting of the FYVE domain to endosomal membranes is regulated by a histidine switch.
    Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13052-7 PMID: 16141328
  8. Structural basis for discrimination of 3-phosphoinositides by pleckstrin homology domains.
    Mol Cell. 2000 Aug;6(2):373-84 PMID: 10983984
  9. Membrane binding domains.
    Biochim Biophys Acta. 2006 Aug;1761(8):805-11 PMID: 16616874
  10. BAR, F-BAR (EFC) and ENTH/ANTH domains in the regulation of membrane-cytosol interfaces and membrane curvature.
    Biochim Biophys Acta. 2006 Aug;1761(8):897-912 PMID: 16938488
  11. Phox homology domains specifically bind phosphatidylinositol phosphates.
    Biochemistry. 2001 Jul 31;40(30):8940-4 PMID: 11467955
  12. Molecular mechanism of membrane targeting by the GRP1 PH domain.
    J Lipid Res. 2008 Aug;49(8):1807-15 PMID: 18469301
  13. Non-canonical interaction of phosphoinositides with pleckstrin homology domains of Tiam1 and ArhGAP9.
    J Biol Chem. 2007 May 4;282(18):13864-74 PMID: 17339315
  14. Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate.
    Structure. 1999 Apr 15;7(4):449-60 PMID: 10196129
  15. Membrane-targeting sequences on AKAP79 bind phosphatidylinositol-4, 5-bisphosphate.
    EMBO J. 1998 Apr 15;17(8):2246-60 PMID: 9545238
  16. Structural determinants of phosphoinositide selectivity in splice variants of Grp1 family PH domains.
    EMBO J. 2004 Oct 1;23(19):3711-20 PMID: 15359279
  17. Membrane recognition by phospholipid-binding domains.
    Nat Rev Mol Cell Biol. 2008 Feb;9(2):99-111 PMID: 18216767
  18. Membrane and juxtamembrane targeting by PH and PTB domains.
    Biochim Biophys Acta. 2006 Aug;1761(8):850-67 PMID: 16807090
  19. Single-molecule fluorescence studies of a PH domain: new insights into the membrane docking reaction.
    Biophys J. 2009 Jan;96(2):566-82 PMID: 19167305
  20. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change.
    Biochem J. 2003 Nov 1;375(Pt 3):531-8 PMID: 12964941
  21. A functional PtdIns(3)P-binding motif.
    Nature. 1998 Jul 30;394(6692):433-4 PMID: 9697765
  22. The endosome fusion regulator early-endosomal autoantigen 1 (EEA1) is a dimer.
    Biochem J. 1999 Mar 1;338 ( Pt 2):539-43 PMID: 10024533
  23. Molecular modeling of the membrane targeting of phospholipase C pleckstrin homology domains.
    Protein Sci. 2003 Sep;12(9):1934-53 PMID: 12930993
  24. The structural basis of novel endosome anchoring activity of KIF16B kinesin.
    EMBO J. 2007 Aug 8;26(15):3709-19 PMID: 17641687
  25. Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates.
    EMBO J. 2004 Oct 13;23(20):3918-28 PMID: 15457207
  26. Pleckstrin domain homology.
    Nature. 1993 May 27;363(6427):309-10 PMID: 8497315
  27. Solution structure of the Vam7p PX domain.
    Biochemistry. 2002 May 14;41(19):5956-62 PMID: 11993989
  28. Pleckstrin homology domains: not just for phosphoinositides.
    Biochem Soc Trans. 2004 Nov;32(Pt 5):707-11 PMID: 15493994
  29. Structural basis of the membrane-targeting and unmasking mechanisms of the radixin FERM domain.
    EMBO J. 2000 Sep 1;19(17):4449-62 PMID: 10970839
  30. SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P.
    Nat Cell Biol. 2001 Jul;3(7):658-66 PMID: 11433298
  31. Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains.
    Mol Cell. 2000 Aug;6(2):385-94 PMID: 10983985
  32. PtdIns4P recognition by Vps74/GOLPH3 links PtdIns 4-kinase signaling to retrograde Golgi trafficking.
    J Cell Biol. 2009 Dec 28;187(7):967-75 PMID: 20026658
  33. The actin-binding protein profilin binds to PIP2 and inhibits its hydrolysis by phospholipase C.
    Science. 1990 Mar 30;247(4950):1575-8 PMID: 2157283
  34. Cellular functions of phosphatidylinositol 3-phosphate and FYVE domain proteins.
    Biochem J. 2001 Apr 15;355(Pt 2):249-58 PMID: 11284710
  35. Molecular mechanism of membrane docking by the Vam7p PX domain.
    J Biol Chem. 2006 Dec 1;281(48):37091-101 PMID: 16984909
  36. Structural and membrane binding analysis of the Phox homology domain of phosphoinositide 3-kinase-C2alpha.
    J Biol Chem. 2006 Dec 22;281(51):39396-406 PMID: 17038310
  37. Membrane binding and subcellular targeting of C2 domains.
    Biochim Biophys Acta. 2006 Aug;1761(8):838-49 PMID: 16945584
  38. Phosphoinositide signaling; from affinity probes to pharmaceutical targets.
    Chem Biol. 2004 May;11(5):619-37 PMID: 15157873
  39. Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes.
    Nat Cell Biol. 2001 Jul;3(7):613-8 PMID: 11433291
  40. Structural mechanism of endosome docking by the FYVE domain.
    Science. 2001 Mar 2;291(5509):1793-6 PMID: 11230696
  41. G-protein signaling through tubby proteins.
    Science. 2001 Jun 15;292(5524):2041-50 PMID: 11375483
  42. Mechanistic basis of differential cellular responses of phosphatidylinositol 3,4-bisphosphate- and phosphatidylinositol 3,4,5-trisphosphate-binding pleckstrin homology domains.
    J Biol Chem. 2007 Nov 2;282(44):32093-105 PMID: 17823121
  43. Solution structure of human sorting nexin 22.
    Protein Sci. 2007 May;16(5):807-14 PMID: 17400918
  44. Multivalent endosome targeting by homodimeric EEA1.
    Mol Cell. 2001 Nov;8(5):947-58 PMID: 11741531
  45. Computer modeling of the membrane interaction of FYVE domains.
    J Mol Biol. 2003 May 2;328(3):721-36 PMID: 12706728
  46. Multivalent mechanism of membrane insertion by the FYVE domain.
    J Biol Chem. 2004 Jan 23;279(4):3050-7 PMID: 14578346
  47. Mechanism of membrane binding of the phospholipase D1 PX domain.
    J Biol Chem. 2004 Dec 24;279(52):54918-26 PMID: 15475361
  48. All phox homology (PX) domains from Saccharomyces cerevisiae specifically recognize phosphatidylinositol 3-phosphate.
    J Biol Chem. 2001 Nov 23;276(47):44179-84 PMID: 11557775
  49. The PX domains of p47phox and p40phox bind to lipid products of PI(3)K.
    Nat Cell Biol. 2001 Jul;3(7):675-8 PMID: 11433300
  50. Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains.
    Science. 1997 Mar 28;275(5308):1927-30 PMID: 9072969
  51. Mechanism of N-WASP activation by CDC42 and phosphatidylinositol 4, 5-bisphosphate.
    J Cell Biol. 2000 Sep 18;150(6):1299-310 PMID: 10995436
  52. The PX-BAR membrane-remodeling unit of sorting nexin 9.
    EMBO J. 2007 Nov 14;26(22):4788-800 PMID: 17948057
  53. FENS-1 and DFCP1 are FYVE domain-containing proteins with distinct functions in the endosomal and Golgi compartments.
    J Cell Sci. 2001 Nov;114(Pt 22):3991-4000 PMID: 11739631
  54. Novel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains?
    Protein Sci. 1996 Nov;5(11):2353-7 PMID: 8931154
  55. Crystal structures of PI3K-C2alpha PX domain indicate conformational change associated with ligand binding.
    BMC Struct Biol. 2008 Feb 29;8:13 PMID: 18312637
  56. GOLPH3 bridges phosphatidylinositol-4- phosphate and actomyosin to stretch and shape the Golgi to promote budding.
    Cell. 2009 Oct 16;139(2):337-51 PMID: 19837035
  57. Structural basis for endosomal targeting by FYVE domains.
    J Biol Chem. 2004 Feb 13;279(7):5958-66 PMID: 14594806
  58. The molecular basis of the differential subcellular localization of FYVE domains.
    J Biol Chem. 2004 Dec 17;279(51):53818-27 PMID: 15452113
  59. Full-length p40phox structure suggests a basis for regulation mechanism of its membrane binding.
    EMBO J. 2007 Feb 21;26(4):1176-86 PMID: 17290225
  60. The Phox (PX) domain proteins and membrane traffic.
    Biochim Biophys Acta. 2006 Aug;1761(8):878-96 PMID: 16782399
  61. Live cell imaging with protein domains capable of recognizing phosphatidylinositol 4,5-bisphosphate; a comparative study.
    BMC Cell Biol. 2009 Sep 21;10:67 PMID: 19769794
  62. Structural and membrane binding analysis of the Phox homology domain of Bem1p: basis of phosphatidylinositol 4-phosphate specificity.
    J Biol Chem. 2007 Aug 31;282(35):25737-47 PMID: 17581820
  63. Phosphatidylinositol 3-phosphate recognition and membrane docking by the FYVE domain.
    Biochim Biophys Acta. 2006 Aug;1761(8):868-77 PMID: 16644267
  64. Membrane insertion of the FYVE domain is modulated by pH.
    Proteins. 2009 Sep;76(4):852-60 PMID: 19296456
  65. Structural basis and mechanism of autoregulation in 3-phosphoinositide-dependent Grp1 family Arf GTPase exchange factors.
    Mol Cell. 2007 Nov 30;28(4):569-83 PMID: 18042453
  66. A putative modular domain present in diverse signaling proteins.
    Cell. 1993 May 21;73(4):629-30 PMID: 8500161
  67. Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function.
    Biochem J. 2009 Apr 1;419(1):1-13 PMID: 19272020
  68. Synthesis and function of 3-phosphorylated inositol lipids.
    Annu Rev Biochem. 2001;70:535-602 PMID: 11395417
  69. Determinants of the endosomal localization of sorting nexin 1.
    Mol Biol Cell. 2005 Apr;16(4):2049-57 PMID: 15673616
  70. PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox).
    Nat Cell Biol. 2001 Jul;3(7):679-82 PMID: 11433301
  71. Mechanistic similarities in docking of the FYVE and PX domains to phosphatidylinositol 3-phosphate containing membranes.
    Prog Lipid Res. 2007 Nov;46(6):315-27 PMID: 17707914
  72. Phosphoinositides in cell regulation and membrane dynamics.
    Nature. 2006 Oct 12;443(7112):651-7 PMID: 17035995
  73. Membrane activity of the phospholipase C-delta1 pleckstrin homology (PH) domain.
    Biochem J. 2005 Jul 15;389(Pt 2):435-41 PMID: 15755258
  74. Structure of the binding site for inositol phosphates in a PH domain.
    EMBO J. 1995 Oct 2;14(19):4676-85 PMID: 7588597
  75. The effector domain of myristoylated alanine-rich C kinase substrate binds strongly to phosphatidylinositol 4,5-bisphosphate.
    J Biol Chem. 2001 Feb 16;276(7):5012-9 PMID: 11053422
  76. Phosphoinositides in constitutive membrane traffic.
    Physiol Rev. 2004 Jul;84(3):699-730 PMID: 15269334
  77. Membrane binding mechanisms of the PX domains of NADPH oxidase p40phox and p47phox.
    J Biol Chem. 2003 Apr 18;278(16):14469-79 PMID: 12556460
  78. Simultaneous binding of PtdIns(4,5)P2 and clathrin by AP180 in the nucleation of clathrin lattices on membranes.
    Science. 2001 Feb 9;291(5506):1051-5 PMID: 11161218
  79. Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate.
    Nature. 1994 Sep 8;371(6493):168-70 PMID: 8072546
  80. Investigation of the binding geometry of a peripheral membrane protein.
    Biochemistry. 2005 Dec 13;44(49):16064-71 PMID: 16331966
  81. FYVE fingers bind PtdIns(3)P.
    Nature. 1998 Jul 30;394(6692):432-3 PMID: 9697764
  82. Phosphatidylinositol 3-phosphate induces the membrane penetration of the FYVE domains of Vps27p and Hrs.
    J Biol Chem. 2002 Jul 19;277(29):26379-88 PMID: 12006563
  83. Mutations in phosphoinositide metabolizing enzymes and human disease.
    Physiology (Bethesda). 2009 Feb;24:8-16 PMID: 19196647
  84. Curvature of clathrin-coated pits driven by epsin.
    Nature. 2002 Sep 26;419(6905):361-6 PMID: 12353027
  85. Solution structure of the PX domain, a target of the SH3 domain.
    Nat Struct Biol. 2001 Jun;8(6):526-30 PMID: 11373621
  86. Alfy, a novel FYVE-domain-containing protein associated with protein granules and autophagic membranes.
    J Cell Sci. 2004 Aug 15;117(Pt 18):4239-51 PMID: 15292400
  87. Crystal structure of the VHS and FYVE tandem domains of Hrs, a protein involved in membrane trafficking and signal transduction.
    Cell. 2000 Feb 18;100(4):447-56 PMID: 10693761
  88. A high-resolution solution structure of a trypanosomatid FYVE domain.
    Protein Sci. 2007 Nov;16(11):2552-9 PMID: 17905827
  89. High-affinity binding of a FYVE domain to phosphatidylinositol 3-phosphate requires intact phospholipid but not FYVE domain oligomerization.
    Biochemistry. 2001 Jul 24;40(29):8581-7 PMID: 11456498
  90. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.
    Nature. 2007 Jul 26;448(7152):439-44 PMID: 17611497
  91. New EMBO members' review: actin cytoskeleton regulation through modulation of PI(4,5)P(2) rafts.
    EMBO J. 2001 Aug 15;20(16):4332-6 PMID: 11500359
  92. The crystal structure of the PX domain from p40(phox) bound to phosphatidylinositol 3-phosphate.
    Mol Cell. 2001 Oct;8(4):829-39 PMID: 11684018
  93. Crystal structure of the yeast Phox homology (PX) domain protein Grd19p complexed to phosphatidylinositol-3-phosphate.
    J Biol Chem. 2003 Dec 12;278(50):50371-6 PMID: 14514667
  94. Signal-dependent membrane targeting by pleckstrin homology (PH) domains.
    Biochem J. 2000 Aug 15;350 Pt 1:1-18 PMID: 10926821
  95. High-resolution structure of the pleckstrin homology domain of protein kinase b/akt bound to phosphatidylinositol (3,4,5)-trisphosphate.
    Curr Biol. 2002 Jul 23;12(14):1256-62 PMID: 12176338
  96. Structural basis of membrane targeting by the Phox homology domain of cytokine-independent survival kinase (CISK-PX).
    J Biol Chem. 2004 Jul 16;279(29):30662-9 PMID: 15126499
  97. Crystal structure of a phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p.
    Cell. 1999 May 28;97(5):657-66 PMID: 10367894
  98. Phosphatidylinositol(3)-phosphate signaling mediated by specific binding to RING FYVE domains.
    Mol Cell. 1998 Jul;2(1):157-62 PMID: 9702203
  99. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
    Nat Rev Genet. 2006 Aug;7(8):606-19 PMID: 16847462
  100. Binding of the PX domain of p47(phox) to phosphatidylinositol 3,4-bisphosphate and phosphatidic acid is masked by an intramolecular interaction.
    EMBO J. 2002 Oct 1;21(19):5057-68 PMID: 12356722
Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.390
Email
tatiana.kutateladze@ucdenver.edu
Published
2010-07-00
Pages
507-13
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC3182472
Subset
IM
Grants
NCI NIH HHS · R01 CA113472 · United States
NIGMS NIH HHS · R01 GM071424 · United States
NIGMS NIH HHS · GM 071424 · United States
NCI NIH HHS · CA 113472 · United States
Databases
PDB
1HYI, 1JOC
External Links
PubMed source DOI: 10.1038/nchembio.390 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2