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{PDOC00710}
{PS00915; PI3_4_KINASE_1}
{PS00916; PI3_4_KINASE_2}
{PS50290; PI3_4_KINASE_3}
{BEGIN}
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* Phosphatidylinositol 3- and 4-kinases catalytic domain signatures and profile *
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Phosphatidylinositol 3-kinase  (PI3-kinase)  (EC 2.7.1.137)  [1] is  an enzyme
that phosphorylates  phosphoinositides on the 3-hydroxyl group of the inositol
ring. The  exact  function  of  the  three  products  of  PI3-kinase - PI-3-P,
PI-3,4-P(2) and PI-3,4,5-P(3) - is not yet known, although it is proposed that
they function  as second messengers in cell signalling. Currently, three forms
of PI3-kinase are known:

 - The  mammalian  enzyme  which is a heterodimer  of a 110 Kd catalytic chain
   (p110) and  an 85  Kd  subunit  (p85)  which allows it to bind to activated
   tyrosine protein kinases.  There are at  least  two different types of p100
   subunits (alpha and beta).
 - Yeast    TOR1/DRR1  and  TOR2/DRR2 [2], PI3-kinases required for cell cycle
   activation. Both are proteins of about 280 Kd.
 - Yeast VPS34 [3], a PI3-kinase involved in vacuolar sorting and segregation.
   VPS34 is a protein of about 100 Kd.
 - Arabidopsis thaliana and soybean VPS34 homologs.

Phosphatidylinositol 4-kinase    (PI4-kinase)  (EC 2.7.1.67) [4] is  an enzyme
that acts  on  phosphatidylinositol  (PI)  in the  first committed step in the
production of  the  second  messenger inositol-1,4,5,-trisphosphate. Currently
the following forms of PI4-kinases are known:

 - Human PI4-kinase alpha.
 - Yeast PIK1, a nuclear protein of 120 Kd.
 - Yeast STT4, a protein of 214 Kd.

The PI3- and PI4-kinases  share  a  well  conserved domain at their C-terminal
section; this domain  seems to be distantly related to the catalytic domain of
protein kinases  [2]. The PI3K/PI4K catalytic domain is divided into an N-lobe
and a   C-lobe   (see   <PDB:4HNE>).   The  N-lobe  contains  a  five-stranded
$antiparallel beta-sheet  core  flanked by a helical hairpin on one side and a
helix on  the  other. The C-lobe contains helices, which form a helical bundle
together with  the  N-lobe helix. The helical bundle is flanked by three beta-
strands and  a helix. Three loops are related to kinase activity, the glycine-
rich G-loop,  the  catalytic loop and the activation loop. The G-loop has been
reported to bind to the phosphate group of nucleotides [5].

Four additional proteins belong to this family:

 - Mammalian FKBP-rapamycin associated protein (FRAP) [6],  which  acts as the
   target for  the  cell-cycle  arrest  and  immunosuppressive  effects of the
   FKBP12-rapamycin complex.
 - Yeast  protein  ESR1  [7] which is required for cell growth, DNA repair and
   meiotic recombination.
 - Yeast protein TEL1 which is involved in controlling telomere length.
 - Yeast  hypothetical protein YHR099w, a  distantly  related  member  of this
   family.
 - Fission yeast hypothetical protein SpAC22E12.16C.

We developed  two  signature  patterns from the best conserved parts of the C-
terminal domain. A profile was also developed that spans the complete domain.

-Consensus pattern: [LIVMFAC]-K-x(1,3)-[DEA]-[DE]-[LIVMCP]-R-Q-[DE]-x(4)-Q
-Sequences known to belong to this class detected by the pattern: ALL,  except
 for yeast YHR099w.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Consensus pattern: [GSET]-x-[AVE]-x(3)-[LIVM]-x(2)-[FYHW]-[LIVM](2)-x-
                    [LIVMFN]-x-D-R-[HNG]-x(2)-N
-Sequences known to belong to this class detected by the pattern: ALL,  except
 for yeast YHR099w.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Sequences known to belong to this class detected by the profile: ALL.
-Other sequence(s) detected in Swiss-Prot: NONE.

-Last update: October 2021 / Profile and text revised.

[ 1] Hiles I.D., Otsu M., Volinia S., Fry M.J., Gout I., Dhand R.,
     Panayotou G., Ruiz-Larrea F., Thompson A., Totty N.F.
     "Phosphatidylinositol 3-kinase: structure and expression of the 110 kd
     catalytic subunit."
     Cell 70:419-429(1992).
     PubMed=1322797
[ 2] Kunz J., Henriquez R., Schneider U., Deuter-Reinhard M., Movva N.R.,
     Hall M.N.
     "Target of rapamycin in yeast, TOR2, is an essential
     phosphatidylinositol kinase homolog required for G1 progression."
     Cell 73:585-596(1993).
     PubMed=8387896
[ 3] Schu P.V., Takegawa K., Fry M.J., Stack J.H., Waterfield M.D., Emr S.D.
     "Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential
     for protein sorting."
     Science 260:88-91(1993).
     PubMed=8385367
[ 4] Garcia-Bustos J.F., Marini F., Stevenson I., Frei C., Hall M.N.
     "PIK1, an essential phosphatidylinositol 4-kinase associated with the
     yeast nucleus."
     EMBO. J. 13:2352-2361(1994).
     PubMed=8194527
[ 5] Zhou Q., Li J., Yu H., Zhai Y., Gao Z., Liu Y., Pang X., Zhang L.,
     Schulten K., Sun F., Chen C.
     "Molecular insights into the membrane-associated phosphatidylinositol
     4-kinase IIalpha."
     Nat. Commun. 5:3552-3552(2014).
     PubMed=24675427; DOI=10.1038/ncomms4552
[ 6] Brown E.J., Albers M.W., Shin T.B., Ichikawa K., Keith C.T.,
     Lane W.S., Schreiber S.L.
     "A mammalian protein targeted by G1-arresting rapamycin-receptor
     complex."
     Nature 369:756-758(1994).
     PubMed=8008069; DOI=10.1038/369756a0
[ 7] Kato R., Ogawa H.
     "An essential gene, ESR1, is required for mitotic cell growth, DNA
     repair and meiotic recombination in Saccharomyces cerevisiae."
     Nucleic Acids Res. 22:3104-3112(1994).
     PubMed=8065923

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