Limits...
How Intrinsic Molecular Dynamics Control Intramolecular Communication in Signal Transducers and Activators of Transcription Factor STAT5.

Langenfeld F, Guarracino Y, Arock M, Trouvé A, Tchertanov L - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.

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.

Show MeSH

Related in: MedlinePlus

Communication in STAT5.(A) Global inter-residue communication represented as 2D interaction networks. Residues are presented by points, communications pathways are depicted by lines. Residues are colored according they communication efficiency (CE), estimated as the number of residues connected by at least on CP, from blue (poor CE) through green and yellow to red (high CE). (B) 3D structural mapping of the inter-residue communication in STAT5. For each protein, non-phosphorylated and phosphorylated, the average MD conformation is shown as a carton. Communication pathways between residues are depicted as connected tips. The STAT5 secondary structures are labeled. Specific tyrosine is denoted as a grey ball.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4696835&req=5

pone.0145142.g008: Communication in STAT5.(A) Global inter-residue communication represented as 2D interaction networks. Residues are presented by points, communications pathways are depicted by lines. Residues are colored according they communication efficiency (CE), estimated as the number of residues connected by at least on CP, from blue (poor CE) through green and yellow to red (high CE). (B) 3D structural mapping of the inter-residue communication in STAT5. For each protein, non-phosphorylated and phosphorylated, the average MD conformation is shown as a carton. Communication pathways between residues are depicted as connected tips. The STAT5 secondary structures are labeled. Specific tyrosine is denoted as a grey ball.

Mentions: To analyze the communication between spatially distant regions or domains of STAT5, we computed for each model all Communication Pathways (CPs). The general landscape of CPs depicted as two-dimensional (2D) graphs mapping communication efficiency (Fig 8A) indicates differences in communication pattern first, between STAT5a and STAT5b and second, between non-phosphorylated and phosphorylated STAT5s.


How Intrinsic Molecular Dynamics Control Intramolecular Communication in Signal Transducers and Activators of Transcription Factor STAT5.

Langenfeld F, Guarracino Y, Arock M, Trouvé A, Tchertanov L - PLoS ONE (2015)

Communication in STAT5.(A) Global inter-residue communication represented as 2D interaction networks. Residues are presented by points, communications pathways are depicted by lines. Residues are colored according they communication efficiency (CE), estimated as the number of residues connected by at least on CP, from blue (poor CE) through green and yellow to red (high CE). (B) 3D structural mapping of the inter-residue communication in STAT5. For each protein, non-phosphorylated and phosphorylated, the average MD conformation is shown as a carton. Communication pathways between residues are depicted as connected tips. The STAT5 secondary structures are labeled. Specific tyrosine is denoted as a grey ball.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696835&req=5

pone.0145142.g008: Communication in STAT5.(A) Global inter-residue communication represented as 2D interaction networks. Residues are presented by points, communications pathways are depicted by lines. Residues are colored according they communication efficiency (CE), estimated as the number of residues connected by at least on CP, from blue (poor CE) through green and yellow to red (high CE). (B) 3D structural mapping of the inter-residue communication in STAT5. For each protein, non-phosphorylated and phosphorylated, the average MD conformation is shown as a carton. Communication pathways between residues are depicted as connected tips. The STAT5 secondary structures are labeled. Specific tyrosine is denoted as a grey ball.
Mentions: To analyze the communication between spatially distant regions or domains of STAT5, we computed for each model all Communication Pathways (CPs). The general landscape of CPs depicted as two-dimensional (2D) graphs mapping communication efficiency (Fig 8A) indicates differences in communication pattern first, between STAT5a and STAT5b and second, between non-phosphorylated and phosphorylated STAT5s.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Biologie et Pharmacologie Appliquée Ecole Normale Supérieure de Cachan, CNRS, Université Paris-Saclay, Cachan, France.

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.

Show MeSH
Related in: MedlinePlus