Phospho-peptide binding domains in S. cerevisiae model organism

Panni, Simona

doi:10.1016/j.biochi.2019.06.005

Cited by 14 publications

(14 citation statements)

References 167 publications

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“…This process is an important reversible regulatory mechanism that plays a key role in the activities of many enzymes, membrane channels and many other proteins in prokaryotic and eukaryotic organisms [6]. Phosphorylation target sites are Ser, Thr, Tyr, His, Pro, Arg, Asp and Cys residues, but this modification mainly happens on Ser, Thr, Tyr and His residues [7]. This PTM includes transferring a phosphate group from adenosine triphosphate to the receptor residues by kinase enzymes.…”

Section: Phosphorylationmentioning

confidence: 99%

Post-translational modification of protein and disease onset- recent advances

Yakubu¹,

Stephen²,

Onuche³

2022

GSC Biol. Pharm. Sci.

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Proteins are the basis of cellular and physiological functioning in living organisms, and the physical and chemical properties of proteins dictate their activities and functions. The primary sequence of a protein is a main determinant of protein folding and final conformation as well as biochemical activity, stability, and half-life. Post-translational modifications (PTMs) are biochemical alterations of amino acids that extend the functional repertoire of proteins. PTMs regulate structural confirmations of proteins, protein-protein interactions and cellular signal transduction central in development. Alterations in the rate and extent of protein synthesis, accuracy, PTMs, and protein turnover are among the major molecular characteristics of some diseases. In this review, the incidence of PTMs disruption on certain disorders was evaluated.

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Section: Phosphorylationmentioning

confidence: 99%

Post-translational modification of protein and disease onset- recent advances

Yakubu¹,

Stephen²,

Onuche³

2022

GSC Biol. Pharm. Sci.

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“…Red1 and Hop1 are involved in recruiting DSB factors to chromosome axis sites, likely via a direct association of DSB factors with Hop1 7, 31, 32, 34, 35 . Mek1, the third component of the RHM complex, is a serine-threonine protein kinase that in addition to its kinase domain, contains a Forkhead-associated (FHA) domain – a phospho-peptide binding domain 36, 37 . Mek1 is similar to Rad53, a key DNA damage checkpoint kinase in mitotically-growing cells 38 .…”

Section: Introductionmentioning

confidence: 99%

“…Mek1, the third component of the RHM complex, is a serine-threonine protein kinase that in addition to its kinase domain, contains a Forkhead-associated (FHA) domain -a phospho-peptide binding domain 36,37 . Mek1 is similar to Rad53, a key DNA damage checkpoint kinase in mitotically-growing cells 38 .…”

Section: Introductionmentioning

confidence: 99%

Studying meiosis in mitosis: Activating the meiosis-specific Red1-Hop1-Mek1 complex in mitotic budding yeast cells

Nivsarkar

Chen

Funk

et al. 2022

Preprint

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In mitosis, sequences on sister chromatids are preferred as DNA repair templates, whereas in meiosis interhomolog-based repair is promoted. The switch of template preference during homologous recombinational (HR) repair of DNA breaks is a defining event in sexual reproduction. This preference is needed to establish linkages between homologous chromosomes that support meiotic chromosome segregation. In budding yeast, a central activity that enforces meiotic interhomolog bias is encoded in a meiosis-specific protein kinase complex, consisting of Red1, Hop1 and Mek1 (i.e., the RHM complex). Activation of Mek1 kinase in meiosis - dictated by complex formation and upstream DNA break-dependent signaling - leads to modification of HR factors and the establishment of interhomolog HR repair bias. How meiotic repair bias is established is a central question with implications for sexual reproduction, genetic diversity and genome stability. Studying the role of the RHM complex in DNA repair is complicated by the fact that Red1 and Hop1 are required for efficient meiotic DNA break formation. Here, we conditionally express RHM components in mitotically-dividing cells to show that these factors can autonomously establish the RHM complex outside of its physiological environment. In vivo analysis is complemented with in vitro biochemical reconstitution to analyze the composition of a Red1-Hop1 subcomplex. The RHM complex can be activated under DNA damaging conditions in mitotically-dividing cells, and activation depends on upstream Mec1 kinase function. We use this system to perform a structure-function analysis of RHM complex formation and Mek1 activation. Finally, we demonstrate that expressing active Mek1 in mitosis leads to rad51Δ-like DNA break sensitivity, suggesting that activation of the RHM complex is sufficient to reconstitute (parts of) its physiological function in mediating HR-based repair. This system should enable querying downstream effects of RHM complex action on DNA repair dynamics and template bias. Human homologs of Red1 and Hop1 are often aberrantly re-expressed in cancer cells. Our system has the potential to inform on (dys)functional effects of these genes on genome stability during human tumorigenesis.

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“…Reversible protein phosphorylation is the main cellular mechanism by which signals from the environment are transmitted to the interior of cells to be translated into responses, both in prokaryotes and eukaryotes ( Av-Gay and Everett, 2000 ; Barthe et al., 2009 ). In the latter, these types of post-translational modifications play a crucial role in most cellular processes ( Panni, 2019 ). Typically, phosphorylation activates the substrate to perform a specific activity or cellular localization and/or transfer the phosphate group to a subsequent effector, initiating a signaling cascade in response to the signal.…”

Section: Introductionmentioning

confidence: 99%

Structure of the Mycobacterium tuberculosis cPknF and conformational changes induced in forkhead-associated regulatory domains

Cabarca

Souza

Oliveira

et al. 2021

Current Research in Structural Biology

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Mycobacterium tuberculosis ( Mtb ) has 11 Serine-Threonine Protein Kinases (STPK) that control numerous physiological processes, including cell growth, cell division, metabolic flow, and transcription. PknF is one of the 11 Mtb STPKs that has, among other substrates, two FHA domains (FHA-1 and FHA-2) of the ATP-Binding Cassette (ABC) transporter Rv1747. Phosphorylation in T152 and T210 located in a non-structured linker that connects Rv1747 FHA domains is considerate to be the regulatory mechanism of the transporter. In this work, we resolved the three-dimensional structure of the PknF catalytic domain (cPknF) in complex with the human kinase inhibitor IKK16. cPknF is conserved when compared to other STPKs but shows specific residues in the binding site where the inhibitor is positioned. In addition, using Small Angle X-Ray Scattering analysis we monitored the behavior of the wild type and three FHA-phosphomimetic mutants in solution, and measured the cPknF affinity for these domains. The kinase showed higher affinity for the non-phosphorylated wild type domain and preference for phosphorylation of T152 inducing the rapprochement of the domains and significant structural changes. The results shed some light on the process of regulating the transporter's activity by phosphorylation and arises important questions about evolution and importance of this mechanism for the bacillus.

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Phospho-peptide binding domains in S. cerevisiae model organism

Cited by 14 publications

References 167 publications

Post-translational modification of protein and disease onset- recent advances

Post-translational modification of protein and disease onset- recent advances

Studying meiosis in mitosis: Activating the meiosis-specific Red1-Hop1-Mek1 complex in mitotic budding yeast cells

Structure of the Mycobacterium tuberculosis cPknF and conformational changes induced in forkhead-associated regulatory domains

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