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

Independent Dynamic Fragments identified in STAT5 proteins.Top: 3D structural mapping of the Independent Dynamic Fragments (IDSs) in STAT5a referred to as Si, where i = 1, 2 …N, is presented on the average conformation as they were found by LFA (A) and by PFD (B) algorithms. Bottom: (C) Graph representation of IDSs found by PFD and LFA in each studied STAT5. Each color specifies an IDS obtained from a seed (LFA) or a predictor (PFD); the IDSs localized on the same structural fragment in various STAT5s may be colored differently according to a number of the first predicted residue in a given IDS.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145142.g007: Independent Dynamic Fragments identified in STAT5 proteins.Top: 3D structural mapping of the Independent Dynamic Fragments (IDSs) in STAT5a referred to as Si, where i = 1, 2 …N, is presented on the average conformation as they were found by LFA (A) and by PFD (B) algorithms. Bottom: (C) Graph representation of IDSs found by PFD and LFA in each studied STAT5. Each color specifies an IDS obtained from a seed (LFA) or a predictor (PFD); the IDSs localized on the same structural fragment in various STAT5s may be colored differently according to a number of the first predicted residue in a given IDS.

Mentions: In phosphorylated and non-phosphorylated STAT5a proteins, the number of IDSs was identical (14) and their positions are well-superimposed (Fig 7C). For a comparative analysis of the IDSs in all STAT5 models, they are referred to as Si, where i = 1, 2…N. Ten IDSs in STAT5a have discrete character (i.e., S1 or S4), the four others show partial overlapping (i.e., S2 or S11), which may be interpreted as fused or duplicated IDSs. The number of IDSs in STAT5b proteins and their character display a strong difference: 9 identified IDSs in STAT5b are distinct and well-separated, while 24 IDSs in p-STAT5b are partially overlapping and may be interpreted as 13 fused IDSs.


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)

Independent Dynamic Fragments identified in STAT5 proteins.Top: 3D structural mapping of the Independent Dynamic Fragments (IDSs) in STAT5a referred to as Si, where i = 1, 2 …N, is presented on the average conformation as they were found by LFA (A) and by PFD (B) algorithms. Bottom: (C) Graph representation of IDSs found by PFD and LFA in each studied STAT5. Each color specifies an IDS obtained from a seed (LFA) or a predictor (PFD); the IDSs localized on the same structural fragment in various STAT5s may be colored differently according to a number of the first predicted residue in a given IDS.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145142.g007: Independent Dynamic Fragments identified in STAT5 proteins.Top: 3D structural mapping of the Independent Dynamic Fragments (IDSs) in STAT5a referred to as Si, where i = 1, 2 …N, is presented on the average conformation as they were found by LFA (A) and by PFD (B) algorithms. Bottom: (C) Graph representation of IDSs found by PFD and LFA in each studied STAT5. Each color specifies an IDS obtained from a seed (LFA) or a predictor (PFD); the IDSs localized on the same structural fragment in various STAT5s may be colored differently according to a number of the first predicted residue in a given IDS.
Mentions: In phosphorylated and non-phosphorylated STAT5a proteins, the number of IDSs was identical (14) and their positions are well-superimposed (Fig 7C). For a comparative analysis of the IDSs in all STAT5 models, they are referred to as Si, where i = 1, 2…N. Ten IDSs in STAT5a have discrete character (i.e., S1 or S4), the four others show partial overlapping (i.e., S2 or S11), which may be interpreted as fused or duplicated IDSs. The number of IDSs in STAT5b proteins and their character display a strong difference: 9 identified IDSs in STAT5b are distinct and well-separated, while 24 IDSs in p-STAT5b are partially overlapping and may be interpreted as 13 fused IDSs.

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