| General information | | DisProt: | DP00713 | | Name: | Lysine-specific demethylase 5A | | Synonym(s): | KDM5A_HUMAN
Histone demethylase JARID1A
Jumonji/ARID domain-containing protein 1A
Retinoblastoma-binding protein 2
RBBP-2
| | First appeared in release: | Release 6.00 (07/01/2012) | | UniProt: | P29375 | | UniGene: | | | SwissProt: | KDM5A_HUMAN | | TrEMBL: | | | NCBI (GI): | | | Source organism: | Homo sapiens (Human) | | Sequence length: | 1690 | | Percent disordered: | 4% | | Homologues: | |
| Native sequence |
10 20 30 40 50 60
| | | | | |
MAGVGPGGYA AEFVPPPECP VFEPSWEEFT DPLSFIGRIR PLAEKTGICK IRPPKDWQPP - 60
FACEVKSFRF TPRVQRLNEL EAMTRVRLDF LDQLAKFWEL QGSTLKIPVV ERKILDLYAL - 120
SKIVASKGGF EMVTKEKKWS KVGSRLGYLP GKGTGSLLKS HYERILYPYE LFQSGVSLMG - 180
VQMPNLDLKE KVEPEVLSTD TQTSPEPGTR MNILPKRTRR VKTQSESGDV SRNTELKKLQ - 240
IFGAGPKVVG LAMGTKDKED EVTRRRKVTN RSDAFNMQMR QRKGTLSVNF VDLYVCMFCG - 300
RGNNEDKLLL CDGCDDSYHT FCLIPPLPDV PKGDWRCPKC VAEECSKPRE AFGFEQAVRE - 360
YTLQSFGEMA DNFKSDYFNM PVHMVPTELV EKEFWRLVSS IEEDVIVEYG ADISSKDFGS - 420
GFPVKDGRRK ILPEEEEYAL SGWNLNNMPV LEQSVLAHIN VDISGMKVPW LYVGMCFSSF - 480
CWHIEDHWSY SINYLHWGEP KTWYGVPSHA AEQLEEVMRE LAPELFESQP DLLHQLVTIM - 540
NPNVLMEHGV PVYRTNQCAG EFVVTFPRAY HSGFNQGYNF AEAVNFCTAD WLPIGRQCVN - 600
HYRRLRRHCV FSHEELIFKM AADPECLDVG LAAMVCKELT LMTEEETRLR ESVVQMGVLM - 660
SEEEVFELVP DDERQCSACR TTCFLSALTC SCNPERLVCL YHPTDLCPCP MQKKCLRYRY - 720
PLEDLPSLLY GVKVRAQSYD TWVSRVTEAL SANFNHKKDL IELRVMLEDA EDRKYPENDL - 780
FRKLRDAVKE AETCASVAQL LLSKKQKHRQ SPDSGRTRTK LTVEELKAFV QQLFSLPCVI - 840
SQARQVKNLL DDVEEFHERA QEAMMDETPD SSKLQMLIDM GSSLYVELPE LPRLKQELQQ - 900
ARWLDEVRLT LSDPQQVTLD VMKKLIDSGV GLAPHHAVEK AMAELQELLT VSERWEEKAK - 960
VCLQARPRHS VASLESIVNE AKNIPAFLPN VLSLKEALQK AREWTAKVEA IQSGSNYAYL - 1020
EQLESLSAKG RPIPVRLEAL PQVESQVAAA RAWRERTGRT FLKKNSSHTL LQVLSPRTDI - 1080
GVYGSGKNRR KKVKELIEKE KEKDLDLEPL SDLEEGLEET RDTAMVVAVF KEREQKEIEA - 1140
MHSLRAANLA KMTMVDRIEE VKFCICRKTA SGFMLQCELC KDWFHNSCVP LPKSSSQKKG - 1200
SSWQAKEVKF LCPLCMRSRR PRLETILSLL VSLQKLPVRL PEGEALQCLT ERAMSWQDRA - 1260
RQALATDELS SALAKLSVLS QRMVEQAARE KTEKIISAEL QKAAANPDLQ GHLPSFQQSA - 1320
FNRVVSSVSS SPRQTMDYDD EETDSDEDIR ETYGYDMKDT ASVKSSSSLE PNLFCDEEIP - 1380
IKSEEVVTHM WTAPSFCAEH AYSSASKSCS QGSSTPRKQP RKSPLVPRSL EPPVLELSPG - 1440
AKAQLEELMM VGDLLEVSLD ETQHIWRILQ ATHPPSEDRF LHIMEDDSME EKPLKVKGKD - 1500
SSEKKRKRKL EKVEQLFGEG KQKSKELKKM DKPRKKKLKL GADKSKELNK LAKKLAKEEE - 1560
RKKKKEKAAA AKVELVKEST EKKREKKVLD IPSKYDWSGA EESDDENAVC AAQNCQRPCK - 1620
DKVDWVQCDG GCDEWFHQVC VGVSPEMAEN EDYICINCAK KQGPVSPGPA PPPSFIMSYK - 1680
LPMEDLKETS
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| Functional narrative |
Function: Histone demethylase that specifically demethylates \'Lys- 4\' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 \'Lys-9\', H3 \'Lys-27\', H3 \'Lys-36\', H3 \'Lys-79\' or H4 \'Lys-20\'. Demethylates trimethylated and dimethylated but not monomethylated H3 \'Lys-4\'. May stimulate transcription mediated by nuclear receptors. May be involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12.
COFACTOR: Binds 1 Fe(2+) ion per subunit (By similarity).
SUBUNIT: Interacts with SUZ12; the interaction is direct (By similarity). Interacts with the viral protein-binding domain of RB1. Interacts with ESR1, MYC, MYCN and LMO2.
Subcellular Location: Nucleus, nucleolus. Note=Occupies promoters of genes involved in RNA metabolism and mitochondrial function (By similarity). Event=Alternative splicing; Named isoforms=2; Name=1; IsoId=P29375-1; Sequence=Displayed; Name=2; IsoId=P29375-2; Sequence=VSP_035746;
DOMAIN: The GSGFP motif is required for the interaction with SUZ12 (By similarity).
SIMILARITY: Belongs to the JARID1 histone demethylase family.
SIMILARITY: Contains 1 ARID domain.
SIMILARITY: Contains 1 JmjC domain.
SIMILARITY: Contains 1 JmjN domain.
SIMILARITY: Contains 3 PHD-type zinc fingers. Sequence=AAB28544.1; Type=Frameshift; Positions=Several; Sequence=BAE06081.1; Type=Erroneous initiation;
WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL=\'http://atlasgeneticsoncology.org/Genes/JARID1AID41033ch12p13.html\';
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| Map of ordered and disordered regions |
Note: 'Mouse' over a region to see the start and stop residues. Click on a region to see detailed information.
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| Region 1 | | Type: | Disordered | | Name: | Loop L1 of ARID domain | | Location: | 103 - 116 | | Length: | 14 | | Region sequence: |
STLKIPVVERKILD | | Modification type: | Fragment
| | PDB: | 2JXJ:A | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Molecular assembly
Molecular recognition effectors
| | Functional subclasses: | Protein-DNA binding
Transactivation (transcriptional activation)
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6; NaCl 100 mM; ARID domain protein fragment 0.4 mM; sodium phosphate 50 mM; 90% H2O/10% D2O)
- Nuclear magnetic resonance (NMR) (280 K; pH: 6.7; ARID domain protein fragment (1:1 ratio with DNA); duplex DNA (synthetic construct); NaCl 100 mM; phosphate buffer 40 mM)
| References:
- Tu S, Teng YC, Yuan C, Wu YT, Chan MY, Cheng AN, Lin PH, Juan LJ, Tsai MD. "The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif." Nat. Struct. Mol. Biol.. 2008; 15(4): 419-21. PubMed: 18270511
| Comments:According to Tu et al (2008), Loop L1 of the ARID domain contains two beta-strands (aa V109-V110 and K113-I114). Residue R112 is involved in DNA binding, and I114 shows a large chemical shift upon DNA binding.
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| Region 2 | | Type: | Disordered | | Name: | Loop L2 of ARID domain | | Location: | 148 - 154 | | Length: | 7 | | Region sequence: |
YLPGKGT | | Modification type: | Fragment
| | PDB: | 2JXJ:A | | Structural/functional type: | Function arises from the disordered state
| | Functional classes: | Molecular recognition effectors
Molecular assembly
| | Functional subclasses: | Transactivation (transcriptional activation)
Protein-DNA binding
| Detection methods:
- Nuclear magnetic resonance (NMR) (293 K; pH: 6; 90% H2O/10% D2O; NaCl 100 mM; protein 0.4 mM; sodium phosphate 50 mM)
- Nuclear magnetic resonance (NMR) (280 K; pH: 6.7; ARID domain protein fragment (1:1 ratio with DNA); duplex DNA (synthetic construct); NaCl 100 mM; phosphate buffer 40 mM)
| References:
- Tu S, Teng YC, Yuan C, Wu YT, Chan MY, Cheng AN, Lin PH, Juan LJ, Tsai MD. "The ARID domain of the H3K4 demethylase RBP2 binds to a DNA CCGCCC motif." Nat. Struct. Mol. Biol.. 2008; 15(4): 419-21. PubMed: 18270511
| Comments:Tu et al (2008) describe large chemical shifts upon DNA binding for Loop L2 of ARID domain, as well as parts of Helix H4 and Helix H5 which flank Loop L2. Particularly mobile residues are W139, S140, L146 of Helix H4, G151, K152, G153 and T154 of Loop L2, and G155 and L158 of Helix H5. Helix H4, Loop L2 and Helix H5 form an "ubiquitous helix-turn-helix DNA binding motif."
DNA-binding residues are R112 (in Loop L1), K152 (in Loop L2), S156 and L157 (in Helix H5).
|
| Region 3 | | Type: | Disordered w/ Residual Structure | | Name: | PHD3 (C-terminal PHD) | | Location: | 1609 - 1659 | | Length: | 51 | | Region sequence: |
VCAAQNCQRPCKDKVDWVQCDGGCDEWFHQVCVGVSPEMAENEDYICINCA | | Modification type: | Complex
Fragment
| | PDB: | 2KGG:A, 2KGI:A, 3GL6:A | | Structural/functional type: | Function arises via a disorder to order transition
| | Functional classes: | Molecular recognition effectors
| | Functional subclasses: | Substrate/ligand binding
Protein-protein binding
Methylation
| Detection methods:
- X-ray crystallography (293 K; pH: 7.5; H3K4me3 peptide; Hepes-Na 0.1 M; iso-propanol 10 %; Jarid1A PHD3 domain (PDB 3GL6); PEG4000 20 %)
- Nuclear magnetic resonance (NMR) (293.2 K; pH: 7; Bacteriophage PF1 (present in solution 2) 12 mb/mL; DTT 5 mM; Jarid1A PHD3 domain (PDB 2KGG; 0.02-0.5 mM; temps 293.2K & 298.2K; in 90% H2O/10% D2O) 0.5 mM; MOPS (present in solution 2) 10 mM; NaCl (present in condition 2) 200 mM; Sodium phosphate 20 mM; Zinc chloride 1 mM)
- Nuclear magnetic resonance (NMR) (293.2 K; pH: 7; Bacteriophage PF1 (present in solution 2) 12 mg/mL; DTT 5 mM; H3(1-9)K4me3 peptide (0.02-0.5 mM) 0.5 mM; Jarid1A PHD3 domain (PDB 2KGI; 0.02-0.5 mM; temps 293.2K & 298.2K; in 90% H2O/10% D2O) 0.5 mM; MOPS (present in solution 2) 10 mM; NaCl (present in condition 2) 200 mM; Sodium phosphate 20 mM; Zinc chloride 1 mM)
| References:
- Wang GG, Song J, Wang Z, Dormann HL, Casadio F, Li H, Luo JL, Patel DJ, Allis CD. "Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger." Nature. 2009; 459(7248): 847-51. PubMed: 19430464
| Comments:Wang et al (2009) observe substantial chemical shifts between free and H3-bound states of the JARID1A C-terminal PHD3 domain, notably, many surface residues from aa C1619 to Y1653.
In JARID1A PHD3-H3(1-9)K4me3 complex, PHD3 aromatic side chains of W1625 and W1635 engage the trimethylated H3K4 peptide; these two residues are highly conserved. Unlike PHD of similar proteins BPTF, ING2 and Yng1, residues V1609 and C1619 of JARID1A do not engage the H3 peptide.
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| Comments |
AV sent 6/19/2012 (PMID:18270511)
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