Inositol 1,3,4,5,6-pentakisphosphate 2-kinase is a distant IPK member with a singular inositide binding site for axial 2-OH recognition.
Inositol phosphates (InsPs) are signaling molecules with multiple roles in cells. In particular (InsP(6)) is involved in mRNA export and editing or chromatin remodeling among other events. InsP(6) accumulates as mixed salts (phytate) in storage tissues of plants and plays a key role in their physiology. Human diets that are exclusively grain-based provide an excess of InsP(6) that, through chelation of metal ions, may have a detrimental effect on human health. Ins(1,3,4,5,6)P(5) 2-kinase (InsP(5) 2-kinase or Ipk1) catalyses the synthesis of InsP(6) from InsP(5) and ATP, and is the only enzyme that transfers a phosphate group to the axial 2-OH of the myo-inositide. We present the first structure for an InsP(5) 2-kinase in complex with both substrates and products. This enzyme presents a singular structural region for inositide binding that encompasses almost half of the protein. The key residues in substrate binding are identified, with Asp368 being responsible for recognition of the axial 2-OH. This study sheds light on the unique molecular mechanism for the synthesis of the precursor of inositol pyrophosphates.
González
Beatriz
B
Grupo de Cristalografía Macromolecular y Biología Estructural, Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, Serrano 119, 28006 Madrid, Spain. xbeatriz@iqfr.csic.es
Baños-Sanz
Jose Ignacio
JI
Villate
Maider
M
Brearley
Charles Alistair
CA
Sanz-Aparicio
Julia
J
D000595:Amino Acid Sequence; D000818:Animals; D017360:Arabidopsis / Q000201:enzymology*; D001665:Binding Sites; D006801:Humans; D007295:Inositol Phosphates / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013379:Substrate Specificity; D014867:Water / Q000737:chemistry*
D007295:Inositol Phosphates; D008024:Ligands; D014867:Water; D017853:Phosphotransferases (Alcohol Group Acceptor); C502806:inositol 1,3,4,5,6-pentakisphosphate 2-kinase
Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3
15299374
Science. 2007 Apr 6;316(5821):106-9
17412958
Nat Biotechnol. 2007 Aug;25(8):874-5
17687363
Org Biomol Chem. 2009 Oct 7;7(19):4029-36
19763307
BMC Struct Biol. 2005 Mar 16;5:6
15771780
Biochem J. 2007 May 1;403(3):381-9
17274762
Plant Physiol. 2007 Jul;144(3):1278-91
17535825
Mol Cell. 2004 Sep 10;15(5):703-11
15350215
Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9
2025413
Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12612-7
16107538
Science. 1999 Jul 2;285(5424):96-100
10390371
J Biol Chem. 2000 Nov 24;275(47):36575-83
10960485
Nat Biotechnol. 2008 May;26(5):496-7; author reply 497-8
18464772
Science. 2003 Jan 3;299(5603):114-6
12434012
Acta Crystallogr A. 2008 Jan;64(Pt 1):112-22
18156677
J Biol Chem. 1987 Aug 25;262(24):11647-50
3040709
Nat Rev Mol Cell Biol. 2001 May;2(5):327-38
11331907
Acta Crystallogr D Biol Crystallogr. 1997 May 1;53(Pt 3):240-55
15299926
J Biol Chem. 1994 Nov 11;269(45):28393-9
7961779
Mol Cell. 2005 Apr 15;18(2):201-12
15837423
Cancer Res. 2005 Sep 15;65(18):8339-49
16166311
Proc Natl Acad Sci U S A. 2008 Jan 29;105(4):1134-9
18195352
Mol Cell Biol. 1991 May;11(5):2852-63
2017180
Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8448-53
15939868
Acta Crystallogr D Biol Crystallogr. 2006 Sep;62(Pt 9):1002-11
16929101
Cell. 2000 Sep 15;102(6):721-9
11030616
Phytochemistry. 2003 Nov;64(6):1033-43
14568069
Trends Plant Sci. 2001 Oct;6(10):458-62
11590064
Mol Cell. 2004 Sep 10;15(5):661-75
15350212
Science. 2003 Jan 3;299(5603):112-4
12434013
Methods Mol Biol. 2007;364:215-30
17172768
J Biol Chem. 2002 Aug 30;277(35):31857-62
12084730
Biochem J. 1991 Apr 15;275 ( Pt 2):485-99
1850990
Mol Cell Biochem. 2009 Aug;328(1-2):155-65
19322641
Nature. 2009 May 21;459(7245):437-41
19404259
FEBS Lett. 2008 May 28;582(12):1731-7
18442482
Biochem J. 2006 Feb 15;394(Pt 1):95-103
16223361
Cancer Genomics Proteomics. 2007 Jan-Feb;4(1):43-51
17726240
Acta Crystallogr Sect F Struct Biol Cryst Commun. 2010 Jan 1;66(Pt 1):102-6
20057083
Nat Rev Mol Cell Biol. 2008 Feb;9(2):151-61
18216771
J Biol Chem. 2000 Aug 11;275(32):24686-92
10827188
Plant J. 2008 Nov;56(4):638-52
18643983
Dev Cell. 2005 Jul;9(1):133-45
15992547
Mol Cell. 2004 Sep 10;15(5):689-701
15350214