EzCatDB: M00118

DB codeM00118
RLCP classification1.15.72000.565
CATH domainDomain 12.30.29.30
Domain 21.10.238.10
Domain 31.10.238.10
Domain 43.20.20.190Catalytic domain
Domain 52.60.40.150
E.C.3.1.4.11
CSA2isd
MACiEM0028

CATH domainRelated DB codes (homologues)
1.10.238.10M00183,M00198,D00151
2.30.29.30M00125,M00183
2.60.40.150M00221,M00183,M00043
3.20.20.190M00183,S00236

Enzyme Name
Swiss-protKEGG

P10688
Protein name1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase delta-1phosphoinositide phospholipase C
triphosphoinositide phosphodiesterase
phosphoinositidase C
1-phosphatidylinositol-4,5-bisphosphate phosphodiesterase
monophosphatidylinositol phosphodiesterase
phosphatidylinositol phospholipase C
PI-PLC
1-phosphatidyl-D-myo-inositol-4,5-bisphosphateinositoltrisphosphohydrolase
SynonymsEC 3.1.4.11
Phosphoinositide phospholipase C
Phospholipase C-delta-1
PLC-delta-1
PLC-III

KEGG pathways
MAP codePathways
MAP00562Inositol phosphate metabolism
MAP04070Phosphatidylinositol signaling system

Swiss-prot:Accession NumberP10688
Entry namePLCD1_RAT
Activity1-phosphatidyl-1D-myo-inositol 4,5- bisphosphate + H(2)O = 1D-myo-inositol 1,4,5-trisphosphate + diacylglycerol.
Subunit
Subcellular location
CofactorBinds 3 calcium ions per subunit. Two of the calcium ions are bound to the C2 domain.


CofactorsSubstratesProductsintermediates
KEGG-idC00076C04637C00001C01245C00165
CompoundCalcium1-Phosphatidyl-D-myo-inositol 4,5-bisphosphateH2OD-myo-Inositol 1,4,5-trisphosphateDiacylglycerol
Typedivalent metal (Ca2+, Mg2+)carbohydrate,lipid,phosphate group/phosphate ionH2Ocarbohydrate,phosphate group/phosphate ioncarbohydrate,lipid
1maiAUnboundUnbound
Bound:I3PUnboundUnbound
1djgB01UnboundUnbound
UnboundUnboundUnbound
1djhB01UnboundUnbound
UnboundUnboundUnbound
1djiB01UnboundUnbound
UnboundUnboundUnbound
1djwB01UnboundUnbound
UnboundUnboundUnbound
1djxB01UnboundUnbound
UnboundUnboundUnbound
1djyB01UnboundUnbound
UnboundUnboundUnbound
1djzB01UnboundUnbound
UnboundUnboundUnbound
1isdB01UnboundUnbound
UnboundUnboundUnbound
2isdB01UnboundUnbound
UnboundUnboundUnbound
1djgA01UnboundUnbound
UnboundUnboundUnbound
1djgB02UnboundUnbound
UnboundUnboundUnbound
1djhA01UnboundUnbound
UnboundUnboundUnbound
1djhB02UnboundUnbound
UnboundUnboundUnbound
1djiA01UnboundUnbound
UnboundUnboundUnbound
1djiB02UnboundUnbound
UnboundUnboundUnbound
1djwA01UnboundUnbound
UnboundUnboundUnbound
1djwB02UnboundUnbound
UnboundUnboundUnbound
1djxA01UnboundUnbound
UnboundUnboundUnbound
1djxB02UnboundUnbound
UnboundUnboundUnbound
1djyA01UnboundUnbound
UnboundUnboundUnbound
1djyB02UnboundUnbound
UnboundUnboundUnbound
1djzA01UnboundUnbound
UnboundUnboundUnbound
1djzB02UnboundUnbound
UnboundUnboundUnbound
1isdA01UnboundUnbound
UnboundUnboundUnbound
1isdB02UnboundUnbound
UnboundUnboundUnbound
1qasA01UnboundUnbound
UnboundUnboundUnbound
1qasB01UnboundUnbound
UnboundUnboundUnbound
1qatA01UnboundUnbound
UnboundUnboundUnbound
1qatB01UnboundUnbound
UnboundUnboundUnbound
2isdA01UnboundUnbound
UnboundUnboundUnbound
2isdB02UnboundUnbound
UnboundUnboundUnbound
1djgA02Analogue:_LAUnbound
UnboundUnboundUnbound
1djgB03Analogue:_LAUnbound
UnboundUnboundUnbound
1djhA02Analogue:_BAUnbound
UnboundUnboundUnbound
1djhB03Analogue:_BAUnbound
UnboundUnboundUnbound
1djiA02Bound:_CAUnbound
UnboundUnboundUnbound
1djiB03Bound:_CAUnbound
UnboundUnboundUnbound
1djwA02Bound:_CAUnbound
UnboundUnboundIntermediate-analogue:CIP
1djwB03Bound:_CAUnbound
UnboundUnboundIntermediate-analogue:CIP
1djxA02Bound:_CAUnbound
Bound:I3PUnboundUnbound
1djxB03Bound:_CAUnbound
Bound:I3PUnboundUnbound
1djyA02Bound:_CAUnbound
Analogue:I2PUnboundUnbound
1djyB03Bound:_CAUnbound
Analogue:I2PUnboundUnbound
1djzA02Bound:_CAUnbound
Analogue:IP2UnboundUnbound
1djzB03Bound:_CAUnbound
Analogue:IP2UnboundUnbound
1isdA02UnboundUnbound
UnboundUnboundUnbound
1isdB03UnboundUnbound
UnboundUnboundUnbound
1qasA02UnboundUnbound
UnboundUnboundUnbound
1qasB02UnboundUnbound
UnboundUnboundUnbound
1qatA02Analogue:_SMUnbound
UnboundUnboundUnbound
1qatB02Analogue:_SMUnbound
UnboundUnboundUnbound
2isdA02UnboundUnbound
UnboundUnboundUnbound
2isdB03UnboundUnbound
UnboundUnboundUnbound
1djgA03UnboundUnbound
UnboundUnboundUnbound
1djgB04UnboundUnbound
UnboundUnboundUnbound
1djhA03UnboundUnbound
UnboundUnboundUnbound
1djhB04UnboundUnbound
UnboundUnboundUnbound
1djiA03UnboundUnbound
UnboundUnboundUnbound
1djiB04UnboundUnbound
UnboundUnboundUnbound
1djwA03UnboundUnbound
UnboundUnboundUnbound
1djwB04UnboundUnbound
UnboundUnboundUnbound
1djxA03UnboundUnbound
UnboundUnboundUnbound
1djxB04UnboundUnbound
UnboundUnboundUnbound
1djyA03UnboundUnbound
UnboundUnboundUnbound
1djyB04UnboundUnbound
UnboundUnboundUnbound
1djzA03UnboundUnbound
UnboundUnboundUnbound
1djzB04UnboundUnbound
UnboundUnboundUnbound
1isdA03UnboundUnbound
UnboundUnboundUnbound
1isdB04UnboundUnbound
UnboundUnboundUnbound
1qasA03UnboundUnbound
UnboundUnboundUnbound
1qasB03UnboundUnbound
UnboundUnboundUnbound
1qatA03UnboundUnbound
UnboundUnboundUnbound
1qatB03UnboundUnbound
UnboundUnboundUnbound
2isdA03UnboundUnbound
UnboundUnboundUnbound
2isdB04UnboundUnbound
UnboundUnboundUnbound

Active-site residues
resource
PDB;1djg, 1djh, 1qat & Swiss-prot;P10688
pdbCatalytic residuesCofactor-binding residues
1maiA

1djgB01

1djhB01

1djiB01

1djwB01

1djxB01

1djyB01

1djzB01

1isdB01

2isdB01

1djgA01

1djgB02

1djhA01

1djhB02

1djiA01

1djiB02

1djwA01

1djwB02

1djxA01

1djxB02

1djyA01

1djyB02

1djzA01

1djzB02

1isdA01

1isdB02

1qasA01

1qasB01

1qatA01

1qatB01

2isdA01

2isdB02

1djgA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djgB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djhA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djhB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djiA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djiB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djwA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djwB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djxA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djxB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djyA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djyB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djzA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djzB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1isdA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1isdB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1qasA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1qasB02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1qatA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1qatB02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
2isdA02HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
2isdB03HIS 311;ASN 312;GLU 341;HIS 356;GLU 390
ASN 312;GLU 341;ASP 343;GLU 390(Calcium binding)
1djgA03

1djgB04

1djhA03

1djhB04

1djiA03

1djiB04

1djwA03

1djwB04

1djxA03

1djxB04

1djyA03

1djyB04

1djzA03

1djzB04

1isdA03

1isdB04

1qasA03

1qasB03

1qatA03

1qatB03

2isdA03

2isdB04


References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[9]Fig. 4d, p.600
[12]Scheme 1A, Fig.9, p.1714-1717
[16]p.11657-11659
[22]p.1292-1294

references
[1]
PubMed ID2424507
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Year1986
Volume864
Pages123-41
AuthorsBernheimer AW, Rudy B
TitleInteractions between membranes and cytolytic peptides.
[2]
PubMed ID1497353
JournalArch Biochem Biophys
Year1992
Volume297
Pages328-33
AuthorsPawelczyk T, Lowenstein JM
TitleRegulation of phospholipase C delta activity by sphingomyelin and sphingosine.
[3]
PubMed ID7811237
JournalBiochem Biophys Res Commun
Year1994
Volume205
Pages1563-71
AuthorsHirata M, Kanematsu T, Sakuma K, Koga T, Watanabe Y, Ozaki S, Yagisawa H
TitleD-myo-inositol 1,4,5-trisphosphate binding domain of phospholipase C-delta 1.
[4]
PubMed ID7893146
JournalArch Biochem Biophys
Year1995
Volume317
Pages331-6
AuthorsTsutsumi T, Kobayashi T, Miyashita M, Watanabe S, Homma Y, Okuyama H
TitleA lysophosphoinositide-specific phospholipase C distinct from other phospholipase C families in rat brain.
[5]
PubMed ID8554502
JournalBiochem J
Year1995
Volume312
Pages661-6
AuthorsPaterson HF, Savopoulos JW, Perisic O, Cheung R, Ellis MV, Williams RL, Katan M
TitlePhospholipase C delta 1 requires a pleckstrin homology domain for interaction with the plasma membrane.
[6]
CommentsX-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 12-130.
Medline ID96107342
PubMed ID8521504
JournalCell
Year1995
Volume83
Pages1037-46
AuthorsFerguson KM, Lemmon MA, Schlessinger J, Sigler PB
TitleStructure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain.
Related PDB1mai
Related Swiss-protP10688
[7]
PubMed ID7479822
JournalProc Natl Acad Sci U S A
Year1995
Volume92
Pages10472-6
AuthorsLemmon MA, Ferguson KM, O'Brien R, Sigler PB, Schlessinger J
TitleSpecific and high-affinity binding of inositol phosphates to an isolated pleckstrin homology domain.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 205-756.
Medline ID96378790
PubMed ID8784353
JournalNat Struct Biol
Year1996
Volume3
Pages788-95
AuthorsGrobler JA, Essen LO, Williams RL, Hurley JH
TitleC2 domain conformational changes in phospholipase C-delta 1.
Related Swiss-protP10688
[9]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 133-756.
Medline ID96186808
PubMed ID8602259
JournalNature
Year1996
Volume380
Pages595-602
AuthorsEssen LO, Perisic O, Cheung R, Katan M, Williams RL
TitleCrystal structure of a mammalian phosphoinositide-specific phospholipase C delta.
Related PDB1isd,2isd
Related Swiss-protP10688
[10]
PubMed ID8602254
JournalNature
Year1996
Volume380
Pages581-3
AuthorsIrvine R
TitlePhospholipid signalling. Taking stock of PI-PLC.
[11]
PubMed ID8810295
JournalJ Biol Chem
Year1996
Volume271
Pages25316-26
AuthorsLomasney JW, Cheng HF, Wang LP, Kuan Y, Liu S, Fesik SW, King K
TitlePhosphatidylinositol 4,5-bisphosphate binding to the pleckstrin homology domain of phospholipase C-delta1 enhances enzyme activity.
[12]
CommentsX-ray crystallography
PubMed ID9048554
JournalBiochemistry
Year1997
Volume36
Pages1704-18
AuthorsEssen LO, Perisic O, Katan M, Wu Y, Roberts MF, Williams RL
TitleStructural mapping of the catalytic mechanism for a mammalian phosphoinositide-specific phospholipase C.
Related PDB1djw,1djx,1djy,1djz
[13]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 133-756.
Medline ID97215812
PubMed ID9062102
JournalBiochemistry
Year1997
Volume36
Pages2753-62
AuthorsEssen LO, Perisic O, Lynch DE, Katan M, Williams RL
TitleA ternary metal binding site in the C2 domain of phosphoinositide-specific phospholipase C-delta1.
Related PDB1djg,1djh,1dji
Related Swiss-protP10688
[14]
PubMed ID9405358
JournalEMBO J
Year1997
Volume16
Pages7287-96
AuthorsUellner R, Zvelebil MJ, Hopkins J, Jones J, MacDougall LK, Morgan BP, Podack E, Waterfield MD, Griffiths GM
TitlePerforin is activated by a proteolytic cleavage during biosynthesis which reveals a phospholipid-binding C2 domain.
[15]
PubMed ID9538021
JournalBiochemistry
Year1998
Volume37
Pages5020-8
AuthorsGrobler JA, Hurley JH
TitleCatalysis by phospholipase C delta1 requires that Ca2+ bind to the catalytic domain, but not the C2 domain.
[16]
PubMed ID9565585
JournalJ Biol Chem
Year1998
Volume273
Pages11650-9
AuthorsEllis MV, James SR, Perisic O, Downes CP, Williams RL, Katan M
TitleCatalytic domain of phosphoinositide-specific phospholipase C (PLC). Mutational analysis of residues within the active site and hydrophobic ridge of plcdelta1.
[17]
PubMed ID9588182
JournalBiochem Biophys Res Commun
Year1998
Volume245
Pages722-8
AuthorsShimohama S, Kamiya S, Fujii M, Ogawa T, Kanamori M, Kawamata J, Imura T, Taniguchi T, Yagisawa H
TitleMutation in the pleckstrin homology domain of the human phospholipase C-delta 1 gene is associated with loss of function.
[18]
PubMed ID9707392
JournalCurr Biol
Year1998
Volume8
PagesR557-9
AuthorsIrvine R
TitleInositol phospholipids: translocation, translocation, translocation.
[19]
PubMed ID10453984
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Year1999
Volume46
Pages91-8
AuthorsPawelczyk T
TitleIsozymes delta of phosphoinositide-specific phospholipase C.
[20]
PubMed ID10917660
JournalBiochem Soc Trans
Year1999
Volume27
Pages652-7
AuthorsYagisawa H, Fujii M, Hirata M
TitlePhospholipase C-delta and related molecules.
[21]
PubMed ID9931017
JournalBiochemistry
Year1999
Volume38
Pages1517-24
AuthorsWang T, Pentyala S, Rebecchi MJ, Scarlata S
TitleDifferential association of the pleckstrin homology domains of phospholipases C-beta 1, C-beta 2, and C-delta 1 with lipid bilayers and the beta gamma subunits of heterotrimeric G proteins.
[22]
PubMed ID11015615
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Year2000
Volume80
Pages1291-335
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TitleStructure, function, and control of phosphoinositide-specific phospholipase C.
[23]
PubMed ID11867528
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Year2002
Volume21
Pages1004-11
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TitleRole of the PLC-related, catalytically inactive protein p130 in GABA(A) receptor function.
[24]
PubMed ID11706040
JournalJ Biol Chem
Year2002
Volume277
Pages3568-75
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TitleMembrane targeting of C2 domains of phospholipase C-delta isoforms.
[25]
PubMed ID12401198
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Year2002
Volume531
Pages28-32
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TitleMultiple roles of pleckstrin homology domains in phospholipase Cbeta function.
[26]
PubMed ID12019260
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Year2002
Volume277
Pages27412-22
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TitleInositol lipid binding and membrane localization of isolated pleckstrin homology (PH) domains. Studies on the PH domains of phospholipase C delta 1 and p130.
[27]
PubMed ID12735994
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Year2003
Volume11
Pages2471-5
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TitleNew aspects of formation of 1,2-cyclic phosphates by phospholipase C-delta1.
[28]
PubMed ID12900402
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Year2003
Volume278
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[29]
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Year2003
Volume125
Pages5000-4
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[30]
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Pages29995-30004
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[32]
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comments
This enzyme is composed of the N-terminal Pleckstrin homology (PH) domain, two EF-hand domains, Catalytic domain, and the C-terminal C2 domain.
The PH domain (PDB;1mai) seems to be important for membrane association (see [5] & [6]).
Although literature [9] & [22] mentioned that calcium ion might activate the 2-hydroxyl group for nucleophilic attack on phosphoryl group, by lowering its pKa, it is against other paper (literature of [6] for BamHI, S00384 in EzCatDB). According to the literature [12], the ion may play a dual role, (1) stablization of the negative charge on the deprotonated 2-hydroxyl group, and (2) stabilization of the transition state.
Based on the literature [9], [12], [16] & [22], the catalytic reaction proceeds as follows:
(1) Glu341, which is bound to the calcium ion, acts as a general base to deprotonate and activate the 2-hydroxyl group of substrate, 1-Phosphatidyl-D-myo-inositol 4,5-bisphosphate (IP2) (see [16]). This activation is assisted by the calcium ion, which stabilizes the negative charge on the 2-hydroxyl group, and His311, Asn312 & Glu390, which stabilize the negative charge on the phosphate group (see [12]).
(2) The activated 2-hydroxyl group makes a nucleophilic attack on phosphodiester, to form an intermediate, cyclic IP3.
(3) His356 acts as a general acid to protonate the leaving diacylglycerole (DAG).
(4) His356, now, acts as a general base to deprotonate a water molecule.
(5) The activated water makes an attack on the phosphate group of the intermediate. Here, the leaving 2-hydroxyl group is stabilized by the calcium ion, and probably protonated by a general acid, Glu341. This hydrolysis might be facilitated by the conformational strain of the intermediate (see [12]).

createdupdated
2005-04-142009-02-26
Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2010)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)

© Computational Biology Research Center, AIST, 2004 All Rights Reserved.