Arginine residues within the DNA binding domain of STAT3 promote intracellular shuttling and phosphorylation of STAT3

Ginter, Torsten; Fahrer, Jörg; Kröhnert, Ulrike; Fetz, Verena; Garrone, Alessio; Stauber, Roland H.; Reichardt, Werner; Müller‐Newen, Gerhard; Kosan, Christian; Heinzel, Thorsten; Krämer, Oliver H.

doi:10.1016/j.cellsig.2014.03.033

Cited by 9 publications

(5 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly the residue R197, R198, and R199 showed the most fluctuations in the energy landscape of the DNA molecule, showing the importance of the C‐terminal Arginines in stabilizing the DNA fluctuations. Previous results on Arginine mutants in the DNA binding domain of STAT3 have shown changes in intracellular shuttling and phosphorylation 80 . This also confirms that point mutations at the DNA binding residues cause a destabilizing effect leading to protein compactness and change in binding potential.…”

Section: Resultssupporting

confidence: 80%

Dynamics and recognition of homeodomain containing protein‐DNA complex of IRX4

Malik,

Jayarathna,

Fisher

et al. 2023

Proteins

View full text Add to dashboard Cite

Iroquois Homeobox 4 (IRX4) belongs to a family of homeobox TFs having roles in embryogenesis, cell specification, and organ development. Recently, large scale genome‐wide association studies and epigenetic studies have highlighted the role of IRX4 and its associated variants in prostate cancer. No studies have investigated and characterized the structural aspect of the IRX4 homeodomain and its potential to bind to DNA. The current study uses sequence analysis, homology modeling, and molecular dynamics simulations to explore IRX4 homeodomain‐DNA recognition mechanisms and the role of somatic mutations affecting these interactions. Using publicly available databases, gene expression of IRX4 was found in different tissues, including prostate, heart, skin, vagina, and the protein expression was found in cancer cell lines (HCT166, HEK293), B cells, ascitic fluid, and brain. Sequence conservation of the homeodomain shed light on the importance of N‐ and C‐terminal residues involved in DNA binding. The specificity of IRX4 homodimer bound to consensus human DNA sequence was confirmed by molecular dynamics simulations, representing the role of conserved amino acids including R145, A194, N195, S190, R198, and R199 in binding to DNA. Additional N‐terminal residues like T144 and G143 were also found to have specific interactions highlighting the importance of N‐terminus of the homeodomain in DNA recognition. Additionally, the effects of somatic mutations, including the conserved Arginine (R145, R198, and R199) residues on DNA binding elucidated the importance of these residues in stabilizing the protein‐DNA complex. Secondary structure and hydrogen bonding analysis showed the roles of specific residues (R145, T191, A194, N195, R198, and R199) in maintaining the homogeneity of the structure and its interaction with DNA. The differences in relative binding free energies of all the mutants shed light on the structural modularity of this protein and the dynamics behind protein‐DNA interaction. We also have predicted that the C‐terminal sequence of the IRX4 homeodomain could act as a potential cell‐penetrating peptide, emphasizing the role these small peptides could play in targeting homeobox TFs.

show abstract

Section: Resultssupporting

confidence: 80%

Dynamics and recognition of homeodomain containing protein‐DNA complex of IRX4

Malik,

Jayarathna,

Fisher

et al. 2023

Proteins

View full text Add to dashboard Cite

show abstract

“…Arginine residues within the DNA binding domain of STAT3 have been found to promote intracellular shuttling and phosphorylation of STAT3 (12). An arginine–glutamine-exchange at the STAT3 moieties R414 and R417 reduces cytokine-dependent tyrosine phosphorylation of STAT3.…”

Section: Letter To Editormentioning

confidence: 99%

Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia

et al. 2015

View full text Add to dashboard Cite

“…Importantly the residue R197, R198 and R199 showed the most fluctuations in the energy landscape of the DNA molecule, showing the importance of the C-terminal Arginines in stabilizing the DNA fluctuations. Previous results on arginine mutants in the DNA binding domain of STAT3 have shown changes in intracellular shuttling and phosphorylation 79 . This also confirms that point mutations at the DNA binding residues causes a destabilizing effect leading to protein compactness and change in binding potential.…”

Section: Hydrogen Bond Analysis Of Protein-dna Complexmentioning

confidence: 96%

Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4

Malik

Gandhi

Batra

2022

Preprint

View full text Add to dashboard Cite

Iroquois Homeobox 4 (IRX4) belongs to a family of homeobox TFs having roles in embryogenesis, cell specification and organ development. Recently, Large scale Genome-Wide Association studies and epigenetic studies have highlighted the role of IRX4 and its associated variants in prostate cancer. No studies have investigated and characterized the structural aspect of the IRX4 homeodomain and its potential to bind to DNA. The current study uses sequence analysis, homology modelling and molecular dynamics simulations to explore IRX4 homeodomain-DNA recognition mechanisms and the role of somatic mutations affecting these interactions. Using publicly available databases, gene expression of IRX4 was found in different tissues, including prostate, heart, skin, vagina, and the protein expression was found in cancer cell lines (HCT166, HEK293), B cells, ascitic fluid and brain. Sequence conservation of the homeodomain shed light on the importance of N- and C-terminal residues involved in DNA binding. The specificity of IRX4 homodimer bound to consensus human DNA sequence was confirmed by molecular dynamics simulations, representing the role of conserved amino acids including R145, A194, N195, S190, R198 and R199 in binding to DNA. Additional N-terminal residues like T144 and G143 were also found to have specific interactions highlighting the importance of N-terminus of the homeodomain in DNA recognition. Additionally, the effects of somatic mutations, including the conserved Arginine (R145, R198 and R199) residues on DNA binding elucidated the importance of these residues in stabilizing the protein-DNA complex. Secondary structure and hydrogen bonding analysis showed the roles of specific residues (R145, T191, A194, N195, R198 and R199) in maintaining the homogeneity of the structure and its interaction with DNA. The differences in relative binding free energies of all the mutants shed light on the structural modularity of this protein and the dynamics behind protein-DNA interaction. We also have predicted that the C-terminal sequence of the IRX4 homeodomain could act as a potential cell-penetrating peptide, emphasizing the role these small peptides could play in targeting homeobox TFs.

show abstract

Arginine residues within the DNA binding domain of STAT3 promote intracellular shuttling and phosphorylation of STAT3

Cited by 9 publications

References 47 publications

Dynamics and recognition of homeodomain containing protein‐DNA complex of IRX4

Dynamics and recognition of homeodomain containing protein‐DNA complex of IRX4

Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia

Dynamics and recognition of homeodomain containing protein-DNA complex of IRX4

Contact Info

Product

Resources

About