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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.

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Related in: MedlinePlus

Secondary structure in STAT5 proteins.Secondary structure assignments for the STAT5 proteins were averaged over the two replicas of MD simulations. For each residue, the proportion of secondary structure type is given as a percentage of the total simulation time and shown with lines of different color: α-helix is in red, 310-helix is in black, β-sheet is in green, and β-bridge is in blue. The STAT5 structural domains are indicated at the top by a colored line (the CCD in blue, the DBD in red, the LD in green, the SH2D in yellow and the C-term tail in grey).
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pone.0145142.g004: Secondary structure in STAT5 proteins.Secondary structure assignments for the STAT5 proteins were averaged over the two replicas of MD simulations. For each residue, the proportion of secondary structure type is given as a percentage of the total simulation time and shown with lines of different color: α-helix is in red, 310-helix is in black, β-sheet is in green, and β-bridge is in blue. The STAT5 structural domains are indicated at the top by a colored line (the CCD in blue, the DBD in red, the LD in green, the SH2D in yellow and the C-term tail in grey).

Mentions: When comparing the secondary structures evolution in STAT5a and STAT5b over MD simulations, we found that the two residues replacement in CCD, A187C and Q188F, causes a slight shift of the helical structures in STAT5b, the reorganization of α1-helix in C-extremity to a 310-helix and the elongation of the α2-helix (Fig 4, S5 Fig). The point replacements in DBD (E391D, C392Y, A427S, V442I and S452C) contribute to a slight shortening of the β-strands b and e, along with a shortening of α-helix α4’ in STA5b. We observed that the five-residues insert (CESAT) in the p-Tail of STAT5b and the series of point replacements (F636Q, N639M, L640F, K644M, S664 and F679Y) in SH2 domain promoted a significant destabilization of the helices αB-αD and stimulated a complete unfolding of the β-sheet C in STAT5b. We stated that these structural effects are the responses of STAT5 on the amino acids replacement (polymorphism) and consequently, may be described as a sequence-dependent structural rearrangement/adjustment having either a local character or a long-distance concerted contribution.


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)

Secondary structure in STAT5 proteins.Secondary structure assignments for the STAT5 proteins were averaged over the two replicas of MD simulations. For each residue, the proportion of secondary structure type is given as a percentage of the total simulation time and shown with lines of different color: α-helix is in red, 310-helix is in black, β-sheet is in green, and β-bridge is in blue. The STAT5 structural domains are indicated at the top by a colored line (the CCD in blue, the DBD in red, the LD in green, the SH2D in yellow and the C-term tail in grey).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0145142.g004: Secondary structure in STAT5 proteins.Secondary structure assignments for the STAT5 proteins were averaged over the two replicas of MD simulations. For each residue, the proportion of secondary structure type is given as a percentage of the total simulation time and shown with lines of different color: α-helix is in red, 310-helix is in black, β-sheet is in green, and β-bridge is in blue. The STAT5 structural domains are indicated at the top by a colored line (the CCD in blue, the DBD in red, the LD in green, the SH2D in yellow and the C-term tail in grey).
Mentions: When comparing the secondary structures evolution in STAT5a and STAT5b over MD simulations, we found that the two residues replacement in CCD, A187C and Q188F, causes a slight shift of the helical structures in STAT5b, the reorganization of α1-helix in C-extremity to a 310-helix and the elongation of the α2-helix (Fig 4, S5 Fig). The point replacements in DBD (E391D, C392Y, A427S, V442I and S452C) contribute to a slight shortening of the β-strands b and e, along with a shortening of α-helix α4’ in STA5b. We observed that the five-residues insert (CESAT) in the p-Tail of STAT5b and the series of point replacements (F636Q, N639M, L640F, K644M, S664 and F679Y) in SH2 domain promoted a significant destabilization of the helices αB-αD and stimulated a complete unfolding of the β-sheet C in STAT5b. We stated that these structural effects are the responses of STAT5 on the amino acids replacement (polymorphism) and consequently, may be described as a sequence-dependent structural rearrangement/adjustment having either a local character or a long-distance concerted contribution.

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