title: Single-Nucleotide Polymorphism of PPARγ, a Protein at the Crossroads of Physiological and Pathological Processes.
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.
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. maria.petrosino@uniromad1.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Petrosino
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. laura.lori@uniroma1.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Lori
authors.affiliation: SSPT-BIOAG-BIOTEC ENEA Casaccia ENEA, 00123 Rome, Italy. alessandra.pasquo@enea.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasquo
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. clorinda.lori@uniroma1.it.
authors.forename: Clorinda
authors.initials: C
authors.lastname: Lori
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. valerio.consalvi@uniroma1.it.
authors.forename: Valerio
authors.initials: V
authors.lastname: Consalvi
authors.affiliation: Department of Physics, University of Rome Tor Vergata and INFN, Via della Ricerca Scientifica 1, 00133 Roma, Italy. Velia.Minicozzi@roma2.infn.it.
authors.forename: Velia
authors.initials: V
authors.lastname: Minicozzi
authors.affiliation: Department of Physics, University of Rome Tor Vergata and INFN, Via della Ricerca Scientifica 1, 00133 Roma, Italy. silvia.morante@roma2.infn.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Morante
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, University of Bari, 70126 Bari, Italy. antonio.laghezza@uniba.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. alessandra.giorgi@uniroma1.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Giorgi
authors.affiliation: Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Via Salaria Km. 29, 300, Monterotondo Stazione, 00015 Roma, Italy. davide.capelli80@gmail.com.
authors.forename: Davide
authors.initials: D
authors.lastname: Capelli
authors.affiliation: Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro, 5, 00185 Rome, Italy. roberta.chiaraluce@uniroma1.it.
authors.forename: Roberta
authors.initials: R
authors.lastname: Chiaraluce
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001665:Binding Sites; D002942:Circular Dichroism; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D047495:PPAR gamma / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D058767:Protein Unfolding / Q000187:drug effects; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014158:Transcription, Genetic; D014508:Urea / Q000494:pharmacology
chemical_list: D008024:Ligands; D047495:PPAR gamma; D014508:Urea
keywords: PPARγ; molecular dynamics; protein stability; single-nucleotide polymorphism