DP00718_A001: Peroxisome proliferator-activated receptor gamma (Isoform 1)FASTA viewXML view

General information
DisProt:DP00718_A001
Name:Peroxisome proliferator-activated receptor gamma (Isoform 1)
Synonym(s):PPARG_HUMAN
Nuclear receptor subfamily 1 group C member 3
PPAR-gamma (Isoform 1)
(Isoform 2 is UniProt canonical)
First appeared in release:Release 5.9 (02/23/2012)
UniProt:P37231-2
UniGene: 
SwissProt: PPARG_HUMAN
TrEMBL:  
NCBI (GI):  
Source organism:Homo sapiens (Human)
Sequence length:477
Percent disordered:64%
Homologues: 


Native sequence

        10         20         30         40         50         60
         |          |          |          |          |          |
MTMVDTEMPF WPTNFGISSV DLSVMEDHSH SFDIKPFTTV DFSSISTPHY EDIPFTRTDP - 60
VVADYKYDLK LQEYQSAIKV EPASPPYYSE KTQLYNKPHE EPSNSLMAIE CRVCGDKASG - 120
FHYGVHACEG CKGFFRRTIR LKLIYDRCDL NCRIHKKSRN KCQYCRFQKC LAVGMSHNAI - 180
RFGRMPQAEK EKLLAEISSD IDQLNPESAD LRALAKHLYD SYIKSFPLTK AKARAILTGK - 240
TTDKSPFVIY DMNSLMMGED KIKFKHITPL QEQSKEVAIR IFQGCQFRSV EAVQEITEYA - 300
KSIPGFVNLD LNDQVTLLKY GVHEIIYTML ASLMNKDGVL ISEGQGFMTR EFLKSLRKPF - 360
GDFMEPKFEF AVKFNALELD DSDLAIFIAV IILSGDRPGL LNVKPIEDIQ DNLLQALELQ - 420
LKLNHPESSQ LFAKLLQKMT DLRQIVTEHV QLLQVIKKTE TDMSLHPLLQ EIYKDLY



Functional narrative    

DP00718_A001 is Isoform 1 of PPAR-gamma. UniProt has selected PPAR-gamma Isoform 2 (DP00718) as the canonical sequence. The isoforms differ in that aa 1-28 of canonical Isoform 2 are missing in Isoform 1.

Function: Receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the receptor binds to a promoter element in the gene for acyl-CoA oxidase and activates its transcription. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. Subunit: Forms a heterodimer with the retinoic acid receptor RXRA called adipocyte-specific transcription factor ARF6. Interacts with NCOA6 coactivator, leading to a strong increase in transcription of target genes. Interacts with coactivator PPARBP, leading to a mild increase in transcription of target genes. Interacts with FAM120B. Interacts with PRDM16 (By similarity). Interacts with NOCA7 in a ligand-inducible manner. Interacts with NCOA1 LXXLL motifs. Interacts with DNTTIP2, MAP2K1/MEK1, PRMT2 and TGFB1I1. P10909:CLU; NbExp=3; IntAct=EBI-781384, EBI-1104674; O60869:EDF1; NbExp=4; IntAct=EBI-781384, EBI-781301; Q6STE5-1:SMARCD3; NbExp=3; IntAct=EBI-781384, EBI-488506; Q6STE5-2:SMARCD3; NbExp=3; IntAct=EBI-781384, EBI-488511.

Region 1: 1-8 Region 2: 9-111 Region 3: 112-174 Region 4: 175-211 Region 5: 212-237 Region 6: 238-278 Region 7: 279-298 Region 8: 299-442 Region 9: 443-452 Region 10: 453-477

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.


Region 1
Type:Disordered
Name:N-terminal
Location:1 - 8
Length:8
Region sequence:

MTMVDTEM

Modification type: Native
PDB:  
Structural/functional type: Relationship to function unknown
Functional classes:  
Functional subclasses:  
Detection methods:
 
References:
There are no documents referencing this region.
Comments:
 



Region 2
Type:Disordered
Name:A/B region
Location:9 - 111
Length:103
Region sequence:

PFWPTNFGISSVDLSVMEDHSHSFDIKPFTTVDFSSISTPHYEDIPFTRTDPVVADYKYD
LKLQEYQSAIKVEPASPPYYSEKTQLYNKPHEEPSNSLMAIEC

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the disordered state
Functional classes: Modification site
Molecular recognition effectors
Functional subclasses: Phosphorylation
Transactivation (transcriptional activation)
Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide ; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829

  2. Fuxreiter M, Simon I, Bondos S. "Dynamic protein-DNA recognition: beyond what can be seen." Trends Biochem. Sci.. 2011; 36(8): 415-23. PubMed: 21620710
Comments:
The entire A/B region is highly deuterated at all time points (15, 50, 150, 500, 1500 seconds), alone or with any additives.

A discussion of the dynamic nature of PPAR-gamma in a "fuzzy" protein-DNA complex is found in Fuxreiter et al (2011).


Region 3
Type:Disordered w/ Residual Structure
Name:DNA binding domain (DBD)
Location:112 - 174
Length:63
Region sequence:

RVCGDKASGFHYGVHACEGCKGFFRRTIRLKLIYDRCDLNCRIHKKSRNKCQYCRFQKCL
AVG

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Protein-DNA binding
Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide ; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
DBD structure: Beta-strands at aa 119-122 and 124-127, alpha-helices at aa 129-140, 157-161 and 163-173.

Most of DBD exhibits moderate levels of deuteration. Ligand-free or in presence of rosiglitazone or GW9662, PPAR-gamma DBD exhibits very low levels of deuteration at aa 136-143 and high levels at aa 146-150. For aa 146-150, deuteration moderates in the presence of the RXR-alpha complex.


Region 4
Type:Disordered w/ Residual Structure
Name:Hinge
Location:175 - 211
Length:37
Region sequence:

MSHNAIRFGRMPQAEKEKLLAEISSDIDQLNPESADL

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Entropic chain
Functional subclasses: Flexible linkers/spacers
Protein-DNA binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Hinge region structure: alpha-helices at aa 188-191 and 197-201.

The hinge region is highly or very highly deuterated at all time points with all additives, except for moderation at aa 170-193 in presence of RXR-alpha complex. Highly deuterated residues 207-211 form the beginning of the Ligand-binding Domain (LBD) and the N-terminal of LBD Helix 1. They are included here due to their dynamism.




Region 5
Type:Ordered
Name:Ligand-binding domain (LBD), Segment A
Location:212 - 237
Length:26
Region sequence:

RALAKHLYDSYIKSFPLTKAKARAIL

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the ordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment A, structure: alpha-helices at aa 206-224 and 230-237.

Low level of deuteration at aa 214-222 for all time points and conditions; low rising to moderate deuteration at aa 225-237 for all conditions, except under two conditions--GW9662 ligand and RXR-alpha complex--where deuteration is moderate rising to high.


Region 6
Type:Disordered w/ Residual Structure
Name:LBD, Seg B
Location:238 - 278
Length:41
Region sequence:

TGKTTDKSPFVIYDMNSLMMGEDKIKFKHITPLQEQSKEVA

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment B structure: beta-sheet at 247-250, alpha-helix at aa 253-258.

LBD, Seg. B is highly deuterated for all time points and conditions, except for aa 240-256 in presence of rosiglitazone where deuteration is moderate rising to high.


Region 7
Type:Disordered w/ Residual Structure
Name:LBD, Seg C
Location:279 - 298
Length:20
Region sequence:

IRIFQGCQFRSVEAVQEITE

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises via a disorder to order transition
Functional classes: Molecular recognition effectors
Functional subclasses: Substrate/ligand binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment C structure: alpha-helix at aa 280-301.

For LBD, Seg.C, deuteration is high at aa 281-287 in ligand-free conditions but very low in presence of rosiglitazone. For aa 290-298, deuteration is moderate rising to high for ligand-free condition, low rising to moderate in presence of GW9662, and very low in presence of rosiglitazone.


Region 8
Type:Ordered
Name:LBD, Seg D
Location:299 - 442
Length:144
Region sequence:

YAKSIPGFVNLDLNDQVTLLKYGVHEIIYTMLASLMNKDGVLISEGQGFMTREFLKSLRK
PFGDFMEPKFEFAVKFNALELDDSDLAIFIAVIILSGDRPGLLNVKPIEDIQDNLLQALE
LQLKLNHPESSQLFAKLLQKMTDL

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the ordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Intraprotein interaction
Substrate/ligand binding
Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment D structure: alpha-helices at aa 208-301, 314-318, 319-329, 350-356, 365-376, 381-393, 403-424 and 431-445; beta-sheets at aa 333-336, 337-341 and 346-349.

LBD, Seg. D deuteration is generally very low to low for all time points in all conditions. For ligand-free, GW9662 and rosiglitazone conditions, deuteration is low rising to moderate at aa 343-351 and 353-363. In presence of RXR-alpha complex, deuteration is very low rising to moderate at aa 353-37 and 419-431.


Region 9
Type:Disordered
Name:LBD, Seg. E
Location:443 - 452
Length:10
Region sequence:

RQIVTEHVQL

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises via an order to disorder transition
Functional classes: Molecular recognition effectors
Functional subclasses: Substrate/ligand binding
Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment E structure: alpha-helices at aaa 431-445 and 446-452.

For ligand-free and rosiglitazone conditions, Seg. E exhibits deuteration very low rising to moderate. In presence of GW9662, deuteration is low rising to high.




Region 10
Type:Disordered
Name:LBD, Seg. F
Location:453 - 477
Length:25
Region sequence:

LQVIKKTETDMSLHPLLQEIYKDLY

Modification type: Native
PDB: 3DZU:D, 3DZY:D, 3E00:D
Structural/functional type: Function arises from the disordered state
Functional classes: Molecular recognition effectors
Functional subclasses: Substrate/ligand binding
Protein-protein binding
Detection methods:
  1. Hydrogen-deuterium exchange (277 K; pH: 8; D2O 10 uL; DNA (in buffer); NaCl (buffer) 200 mM; PPAR-gamma (alone or with ligand and/or DNA or RXR-alpha complex) 18 uM; rosiglitazone or GW9662 (ligand) 144 uM; RXR-alpha complex (RXR-alpha, rosiglitazone, retinoic acid and PPRE DNA); Tris (buffer) 50 mM)

  2. X-ray crystallography (277 K; pH: 6.5; 9-cis Retinoic Acid; buffer (15-18% PEG 3350, 25mM MgCl2, 100mM NH4Cl, 5mM DTT and 0.1M MES,); DNA; NCOA2 Peptide; PPAR-gamma; rosiglitazone or GW9662 or BVT.13 (ligand); RXR-alpha (binding partner fragment))
References:
  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829
Comments:
Ligand-binding domain (LBD), Segment F structure: alpha-helix at aa 467-474.

LBD, Seg.F deuteration is very high or high for all time points in all conditions, except aa 472-477 in presence of rosiglitazone where deuteration is moderate rising to very high.


References

  1. Chandra V, Huang P, Hamuro Y, Raghuram S, Wang Y, Burris TP, Rastinejad F. "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA." Nature. 2008; 456(7220): 350-6. PubMed: 19043829



Comments


Verification request sent 2-21-2012 (PMID: 19043829)


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