title: How Intrinsic Molecular Dynamics Control Intramolecular Communication in Signal Transducers and Activators of Transcription Factor STAT5.
abstract: Signal Transducer and Activator of Transcription STAT5 is a key mediator of cell proliferation, differentiation and survival. While STAT5 activity is tightly regulated in normal cells, its constitutive activation directly contributes to oncogenesis and is associated with a broad range of hematological and solid tumor cancers. Therefore the development of compounds able to modulate pathogenic activation of this protein is a very challenging endeavor. A crucial step of drug design is the understanding of the protein conformational features and the definition of putative binding site(s) for such modulators. Currently, there is no structural data available for human STAT5 and our study is the first footprint towards the description of structure and dynamics of this protein. We investigated structural and dynamical features of the two STAT5 isoforms, STAT5a and STAT5b, taken into account their phosphorylation status. The study was based on the exploration of molecular dynamics simulations by different analytical methods. Despite the overall folding similarity of STAT5 proteins, the MD conformations display specific structural and dynamical features for each protein, indicating first, sequence-encoded structural properties and second, phosphorylation-induced effects which contribute to local and long-distance structural rearrangements interpreted as allosteric event. Further examination of the dynamical coupling between distant sites provides evidence for alternative profiles of the communication pathways inside and between the STAT5 domains. These results add a new insight to the understanding of the crucial role of intrinsic molecular dynamics in mediating intramolecular signaling in STAT5. Two pockets, localized in close proximity to the phosphotyrosine-binding site and adjacent to the channel for communication pathways across STAT5, may constitute valid targets to develop inhibitors able to modulate the function-related communication properties of this signaling protein.
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.|Centre de Mathématiques et de Leurs applications, Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Langenfeld
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Guarracino
authors.affiliation: Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Arock
authors.affiliation: Centre de Mathématiques et de Leurs applications, Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Trouvé
authors.affiliation: Centre de Mathématiques et de Leurs applications, Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.
authors.forename: Luba
authors.initials: L
authors.lastname: Tchertanov
mesh_terms: D001665:Binding Sites / Q000235:genetics; D006801:Humans; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation / Q000235:genetics; D019000:Phosphotyrosine / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D019000:Phosphotyrosine