Molecular simulation of the interaction mechanism between CodY protein and DNA in Lactococcus lactis

Yuan, Linchen; Wu, Hao; Zhao, Yue; Qin, Xiaoqiong; Li, Yanni

doi:10.1007/s11705-018-1737-4

Cited by 6 publications

(4 citation statements)

References 23 publications

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“…Hydrogen bonds were analyzed between the IRX4 homeodomain‐DNA complex to find important residues involved in hydrogen bonding. The key criteria for this analysis were as previously reported 78 . A total of 7 hydrogen bonds were observed at the protein‐DNA interface for the WT IRX4 protein as reported in Table 4.…”

Section: Resultsmentioning

confidence: 99%

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

Malik,

Jayarathna,

Fisher

et al. 2023

Proteins

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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.

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Section: Resultsmentioning

confidence: 99%

“…The key criteria for this analysis were as previously reported. 78 A total of 7 hydrogen bonds were observed at the protein-DNA interface for the WT IRX4 protein as reported in Table 4. The hydrogen bonds are illustrated as donor-acceptor bonds between DNA and protein.…”

Section: Hydrogen Bond Analysis Of Protein-dna Complexmentioning

confidence: 99%

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

“…Hydrogen bonds were analyzed between the IRX4 homeodomain-DNA complex to find important residues involved in hydrogen bonding. The key criteria for this analysis were as previously reported 77 . A total of 7 hydrogen bonds were observed at the protein-DNA interface for the WT IRX4 protein as reported in Table 4.…”

Section: Hydrogen Bond Analysis Of Protein-dna Complexmentioning

confidence: 99%

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

Malik

Gandhi

Batra

2022

Preprint

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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.

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“…The single base change replaced the charged arginine residue at that position in CodY with a noncharged cysteine residue, so we renamed L. lactis MG⌬pepV* as L. lactis MG⌬pepVcodY R218C , which is used through the rest of this article. Yuan et al (19), in their molecular docking and molecular dynamics simulations study, predicted that L. lactis CodY Arg 218 plays a vital role in DNA binding of the protein. When B. subtilis CodY arginine residue 214 (Arg 214 , corresponding to Arg 218 of L. lactis) was changed into a glutamate residue, CodY DNA binding ability was strongly affected (20).…”

Section: Figmentioning

confidence: 99%

Lysis of a Lactococcus lactis Dipeptidase Mutant and Rescue by Mutation in the Pleiotropic Regulator CodY

Hernandez-Valdes

Kuipers

2020

Appl Environ Microbiol

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Lactococcus lactis subsp. cremoris MG1363 is a model for the lactic acid bacteria (LAB) used in the dairy industry. The proteolytic system, consisting of a proteinase, several peptide and amino acid uptake systems, and a host of intracellular peptidases, plays a vital role in nitrogen metabolism and is of eminent importance for flavor formation in dairy products. The dipeptidase PepV functions in the last stages of proteolysis. A link between nitrogen metabolism and peptidoglycan (PG) biosynthesis was underlined by the finding that deletion of the dipeptidase gene pepV (creating strain MGΔpepV) resulted in a prolonged lag phase when the mutant strain was grown with a high concentration of glycine. In addition, most MGΔpepV cells lyse and have serious defects in their shape. This phenotype is due to a shortage of alanine, since adding alanine can rescue the growth and shape defects. Strain MGΔpepV is more resistant to vancomycin, an antibiotic targeting peptidoglycan d-Ala–d-Ala ends, which confirmed that MGΔpepV has an abnormal PG composition. A mutant of MGΔpepV was obtained in which growth inhibition and cell shape defects were alleviated. Genome sequencing showed that this mutant has a single point mutation in the codY gene, resulting in an arginine residue at position 218 in the DNA-binding motif of CodY being replaced by a cysteine residue. Thus, this strain was named MGΔpepVcodYR218C. Transcriptome sequencing (RNA-seq) data revealed a dramatic derepression in peptide uptake and amino acid utilization in MGΔpepVcodYR218C. A model of the connections among PepV activity, CodY regulation, and PG synthesis of L. lactis is proposed. IMPORTANCE Precise control of peptidoglycan synthesis is essential in Gram-positive bacteria for maintaining cell shape and integrity as well as resisting stresses. Although neither the dipeptidase PepV nor alanine is essential for L. lactis MG1363, adequate availability of either ensures proper cell wall synthesis. We broaden the knowledge about the dipeptidase PepV, which acts as a linker between nitrogen metabolism and cell wall synthesis in L. lactis.

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Molecular simulation of the interaction mechanism between CodY protein and DNA in Lactococcus lactis

Cited by 6 publications

References 23 publications

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

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

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

Lysis of a Lactococcus lactis Dipeptidase Mutant and Rescue by Mutation in the Pleiotropic Regulator CodY

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