PMID- 10195690
OWN - NLM
STAT- MEDLINE
DCOM- 19990706
LR  - 20220310
IS  - 0303-7207 (Print)
IS  - 0303-7207 (Linking)
VI  - 147
IP  - 1-2
DP  - 1999 Jan 25
TI  - Conserved amino acids in the ligand-binding and tau(i) domains of the peroxisome 
      proliferator-activated receptor alpha are necessary for heterodimerization with
      RXR.
PG  - 37-47
AB  - The peroxisome proliferator-activated receptors (PPARs) are members of the
      nuclear hormone receptor superfamily. These ligand-activated transcription
      factors are implicated in the regulation of lipid metabolism and adipocyte
      differentiation and in the regulation of anti-inflammatory processes. In order to
      bind to DNA and activate transcription PPAR requires the formation of
      heterodimers with the retinoid X receptor (RXR). We have previously reported that
      replacement of a single leucine by an arginine at position 433 of hPPAR alpha
      (L433R), located in a highly conserved region of the ninth heptad repeat of a
      leucine-zipper-like motif in the ligand binding domain, abolished
      heterodimerization of PPAR with RXR and hence its trans-activating capacity. The 
      aim of our present work was to investigate if other conserved amino acids of the 
      ligand binding domain are important for heterodimerization of PPAR with RXR. We
      found that conserved leucines, L370 and L391, in a leucine-zipper-like motif of
      hPPAR alpha, as well as a highly conserved aspartic acid (D304) in the tau(i)
      domain are necessary for heterodimerization with RXR. In contrast, mutations of
      non-conserved amino acids within the leucine-zipper-like motif do not affect
      PPAR:RXR heterodimerization. Surprisingly, we found that some mutants deficient
      in heterodimerization with RXR (hPPAR alpha-L370R and -L391R) were still
      functional on specific peroxisome proliferator-activator response elements
      (PPREs). Both mutants could trans-activate on a PPRE from the P450 cytochrome
      promoter CYP4A1, whereas only the hPPAR alpha-L391R mutant could trans-activate
      from the acyl-CoA oxidase PPRE (ACOA) and, when stimulated with the peroxisome
      proliferator Wy14643, also from the bifunctional enzyme PPRE. We therefore
      hypothesize either that: (i) these mutants might be able to heterodimerize with a
      protein other than RXR and the affinity for this novel partner may depend on the 
      nature of the PPRE and to some degree on the choice of the activator, or
      alternatively; (ii) that additional nuclear proteins might compensate in vivo for
      the decreased binding of RXR to these mutant PPARs observed in vitro.
FAU - Gorla-Bajszczak, A
AU  - Gorla-Bajszczak A
AD  - Division d'Endocrinologie et Diabetologie, Hopital Cantonal Universitaire de
      Geneve, Geneva, Switzerland.
FAU - Juge-Aubry, C
AU  - Juge-Aubry C
FAU - Pernin, A
AU  - Pernin A
FAU - Burger, A G
AU  - Burger AG
FAU - Meier, C A
AU  - Meier CA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Ireland
TA  - Mol Cell Endocrinol
JT  - Molecular and cellular endocrinology
JID - 7500844
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Ligands)
RN  - 0 (Pyrimidines)
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 30KYC7MIAI (Aspartic Acid)
RN  - 86C4MRT55A (pirinixic acid)
RN  - 9007-49-2 (DNA)
RN  - 9035-51-2 (Cytochrome P-450 Enzyme System)
RN  - EC 1.- (Mixed Function Oxygenases)
RN  - EC 1.- (Oxidoreductases)
RN  - EC 1.14.15.3 (Cytochrome P-450 CYP4A)
RN  - EC 1.3.3.6 (Acyl-CoA Oxidase)
RN  - GMW67QNF9C (Leucine)
SB  - IM
MH  - Acyl-CoA Oxidase
MH  - Amino Acid Sequence
MH  - Aspartic Acid/genetics/metabolism
MH  - Conserved Sequence/genetics/*physiology
MH  - Cytochrome P-450 CYP4A
MH  - Cytochrome P-450 Enzyme System/genetics
MH  - DNA/metabolism
MH  - DNA-Binding Proteins/chemistry/genetics/metabolism
MH  - Dimerization
MH  - Leucine/genetics/metabolism
MH  - Leucine Zippers/genetics
MH  - Ligands
MH  - Mixed Function Oxygenases/genetics
MH  - Molecular Sequence Data
MH  - Mutation
MH  - Oxidoreductases/genetics
MH  - Promoter Regions, Genetic/genetics
MH  - Protein Binding
MH  - Pyrimidines/pharmacology
MH  - Receptors, Cytoplasmic and Nuclear/chemistry/genetics/*metabolism
MH  - Receptors, Retinoic Acid/*metabolism
MH  - Response Elements/genetics
MH  - Retinoid X Receptors
MH  - Trans-Activators/chemistry/genetics/metabolism
MH  - Transcription Factors/chemistry/genetics/*metabolism
EDAT- 1999/04/09 00:00
MHDA- 1999/04/09 00:01
CRDT- 1999/04/09 00:00
PHST- 1999/04/09 00:00 [pubmed]
PHST- 1999/04/09 00:01 [medline]
PHST- 1999/04/09 00:00 [entrez]
AID - S0303-7207(98)00217-2 [pii]
AID - 10.1016/s0303-7207(98)00217-2 [doi]
PST - ppublish
SO  - Mol Cell Endocrinol. 1999 Jan 25;147(1-2):37-47. doi:
      10.1016/s0303-7207(98)00217-2.