Natural helix 9 mutants of PPARγ differently affect its transcriptional activity.
Adipose tissue
FPLD3
Lipodystrophy
Nuclear receptor
PPARG
Journal
Molecular metabolism
ISSN: 2212-8778
Titre abrégé: Mol Metab
Pays: Germany
ID NLM: 101605730
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
22
10
2018
revised:
05
12
2018
accepted:
11
12
2018
pubmed:
1
1
2019
medline:
26
11
2019
entrez:
1
1
2019
Statut:
ppublish
Résumé
The nuclear receptor PPARγ is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPARγ induces terminal differentiation of several epithelial cell lineages, including colon epithelia. Loss-of-function mutations in PPARG result in familial partial lipodystrophy subtype 3 (FPDL3), a rare condition characterized by aberrant adipose tissue distribution and severe metabolic complications, including diabetes. Mutations in PPARG have also been reported in sporadic colorectal cancers, but the significance of these mutations is unclear. Studying these natural PPARG mutations provides valuable insights into structure-function relationships in the PPARγ protein. We functionally characterized a novel FPLD3-associated PPARγ L451P mutation in helix 9 of the ligand binding domain (LBD). Interestingly, substitution of the adjacent amino acid K450 was previously reported in a human colon carcinoma cell line. We performed a detailed side-by-side functional comparison of these two PPARγ mutants. PPARγ L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXRα heterodimerisation and subsequent DNA binding, but not in DBD-LBD interdomain communication. The K450Q mutant displays none of these functional defects. Other colon cancer-associated PPARγ mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity. Amino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPARγ mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPARγ mutations on the other hand may play a role in colon cancer onset and progression, but this is not due to their effects on the most well-studied functional characteristics of PPARγ.
Identifiants
pubmed: 30595551
pii: S2212-8778(18)31027-5
doi: 10.1016/j.molmet.2018.12.005
pmc: PMC6358588
pii:
doi:
Substances chimiques
PPAR gamma
0
PPARG protein, human
0
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
115-127Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
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