Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes

Int J Mol Sci. 2017 Feb 10;18(2):361. doi: 10.3390/ijms18020361.

Abstract

Genome polymorphisms are responsible for phenotypic differences between humans and for individual susceptibility to genetic diseases and therapeutic responses. Non-synonymous single-nucleotide polymorphisms (nsSNPs) lead to protein variants with a change in the amino acid sequence that may affect the structure and/or function of the protein and may be utilized as efficient structural and functional markers of association to complex diseases. This study is focused on nsSNP variants of the ligand binding domain of PPARγ a nuclear receptor in the superfamily of ligand inducible transcription factors that play an important role in regulating lipid metabolism and in several processes ranging from cellular differentiation and development to carcinogenesis. Here we selected nine nsSNPs variants of the PPARγ ligand binding domain, V290M, R357A, R397C, F360L, P467L, Q286P, R288H, E324K, and E460K, expressed in cancer tissues and/or associated with partial lipodystrophy and insulin resistance. The effects of a single amino acid change on the thermodynamic stability of PPARγ, its spectral properties, and molecular dynamics have been investigated. The nsSNPs PPARγ variants show alteration of dynamics and tertiary contacts that impair the correct reciprocal positioning of helices 3 and 12, crucially important for PPARγ functioning.

Keywords: PPARγ; molecular dynamics; protein stability; single-nucleotide polymorphism.

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Binding Sites
  • Circular Dichroism
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • PPAR gamma / chemistry*
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Polymorphism, Single Nucleotide*
  • Protein Binding
  • Protein Conformation
  • Protein Interaction Domains and Motifs
  • Protein Unfolding / drug effects
  • Structure-Activity Relationship
  • Thermodynamics
  • Transcription, Genetic
  • Urea / pharmacology

Substances

  • Ligands
  • PPAR gamma
  • Urea