Natural helix 9 mutants of PPAR? differently affect its transcriptional activity.

ABSTRACT: OBJECTIVE:The nuclear receptor PPAR? is the master regulator of adipocyte differentiation, distribution, and function. In addition, PPAR? 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 PPAR? protein. We functionally characterized a novel FPLD3-associated PPAR? 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. METHODS:We performed a detailed side-by-side functional comparison of these two PPAR? mutants. RESULTS:PPAR? L451P shows multiple intermolecular defects, including impaired cofactor binding and reduced RXR? 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 PPAR? mutants displayed diverse phenotypes, ranging from complete loss of activity to wildtype activity. CONCLUSIONS:Amino acid changes in helix 9 can differently affect LBD integrity and function. In addition, FPLD3-associated PPAR? mutations consistently cause intra- and/or intermolecular defects; colon cancer-associated PPAR? 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 PPAR?.

SUBMITTER: Broekema MF 

PROVIDER: S-EPMC6358588 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature