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  1. Article ; Online: Protein lysine methylation in the regulation of anoxia tolerance in the red eared slider turtle, Trachemys scripta elegans.

    Biggar, Kyle K

    Comparative biochemistry and physiology. Part D, Genomics & proteomics

    2020  Volume 34, Page(s) 100660

    Abstract: The red eared slider turtle (Trachemys scripta elegans) is a champion vertebrate facultative anaerobe, capable of surviving for several months under conditions of exceptionally low oxygen availability. The ability of the turtle to facilitate this ... ...

    Abstract The red eared slider turtle (Trachemys scripta elegans) is a champion vertebrate facultative anaerobe, capable of surviving for several months under conditions of exceptionally low oxygen availability. The ability of the turtle to facilitate this impressive tolerance to oxygen restriction is accomplished through a dramatic reduction in non-essential cellular processes. This is done in an attempt to conserve limited ATP stores and match demand in the anoxic state, with ATP supplied primarily through anaerobic glycolysis. Determining both the non-essential and the essential cellular processes that are deemed to be anoxia-responsive in the turtle has been an intense area of study over the past few decades. As a result, recent advancements have established the influence of global metabolic controls, such as post-transcriptional and post-translational regulation of gene expression in anoxia adaptation. A remaining question is whether or not epigenetic-level regulatory mechanisms are also utilized to allow for local control over gene expression. Recently, research has begun to document lysine methylation as an anoxia-responsive post-translational histone modification, as the activities of a number of methyl-lysine regulatory enzymes are extraordinarily sensitive to oxygen availability. As a result, oxygen-dependent methyl-lysine regulatory enzymes have been of particular interest to several recent studies of animal oxygen sensitivity, including the freshwater turtle. This review will introduce the concept of lysine methylation as an oxygen-sensitive protein modification as well as a prospectus on how this modification may contribute to anoxia tolerance in the turtle.
    MeSH term(s) Adaptation, Physiological ; Animals ; Gene Expression Regulation ; Hypoxia/physiopathology ; Lysine/chemistry ; Methylation ; Protein Processing, Post-Translational ; Turtles
    Chemical Substances Lysine (K3Z4F929H6)
    Language English
    Publishing date 2020-02-01
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2212119-5
    ISSN 1878-0407 ; 1744-117X
    ISSN (online) 1878-0407
    ISSN 1744-117X
    DOI 10.1016/j.cbd.2020.100660
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification of in vitro JMJD lysine demethylase candidate substrates via systematic determination of substrate preference.

    Hoekstra, Matthew / Biggar, Kyle K

    Analytical biochemistry

    2021  Volume 633, Page(s) 114429

    Abstract: A major regulatory influence over gene expression is the dynamic post translational methylation of histone proteins, with major implications from both lysine methylation and demethylation. The KDM5/JARID1 sub-family of Fe(II)/2-oxoglutarate dependent ... ...

    Abstract A major regulatory influence over gene expression is the dynamic post translational methylation of histone proteins, with major implications from both lysine methylation and demethylation. The KDM5/JARID1 sub-family of Fe(II)/2-oxoglutarate dependent lysine-specific demethylases is, in part, responsible for the removal of tri/dimethyl modifications from lysine 4 of histone H3 (i.e., H3K4me3/2), a mark associated with active gene expression. Although the relevance of KDM5 activity to disease progression has been primarily established through its ability to regulate gene expression via histone methylation, there is evidence that these enzymes may also target non-histone proteins. To aid in the identification of new non-histone substrates, we examined KDM5A in vitro activity towards a library of 180 permutated peptide substrates derived from the H3K4me3 sequence. From this data, a recognition motif was identified and used to predict candidate KDM5A substrates from the methyllysine proteome. High-ranking candidate substrates were then validated for in vitro KDM5A activity using representative trimethylated peptides. Our approach correctly identified activity towards 90% of high-ranked substrates. Here, we have demonstrated the usefulness of our method in identifying candidate substrates that is applicable to any Fe(II)- and 2-oxoglutarate dependent demethylase.
    MeSH term(s) Ferrous Compounds/chemistry ; Ferrous Compounds/metabolism ; Humans ; Ketoglutaric Acids/chemistry ; Ketoglutaric Acids/metabolism ; Retinoblastoma-Binding Protein 2/analysis ; Retinoblastoma-Binding Protein 2/metabolism ; Substrate Specificity
    Chemical Substances Ferrous Compounds ; Ketoglutaric Acids ; KDM5A protein, human (EC 1.14.11.-) ; Retinoblastoma-Binding Protein 2 (EC 1.14.11.27)
    Language English
    Publishing date 2021-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1110-1
    ISSN 1096-0309 ; 0003-2697
    ISSN (online) 1096-0309
    ISSN 0003-2697
    DOI 10.1016/j.ab.2021.114429
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Deconvoluting complex protein interaction networks through reductionist strategies in peptide biochemistry: Modern approaches and research questions.

    Lukinović, Valentina / Biggar, Kyle K

    Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology

    2021  Volume 256, Page(s) 110616

    Abstract: Following the decoding of the first human genome, researchers have vastly improved their understanding of cell biology and its regulation. As a result, it has become clear that it is not merely genetic information, but the aberrant changes in the ... ...

    Abstract Following the decoding of the first human genome, researchers have vastly improved their understanding of cell biology and its regulation. As a result, it has become clear that it is not merely genetic information, but the aberrant changes in the functionality and connectivity of its encoded proteins that drive cell response to periods of stress and external cues. Therefore, proper utilization of refined methods that help to describe protein signalling or regulatory networks (i.e., functional connectivity), can help us understand how change in the signalling landscape effects the cell. However, given the vast complexity in 'how and when' proteins communicate or interact with each other, it is extremely difficult to define, characterize, and understand these interaction networks in a tangible manner. Herein lies the challenge of tackling the functional proteome; its regulation is encoded in multiple layers of interaction, chemical modification and cell compartmentalization. To address and refine simple research questions, modern reductionist strategies in protein biochemistry have successfully used peptide-based experiments; their summation helping to simplify the overall complexity of these protein interaction networks. In this way, peptides are powerful tools used in fundamental research that can be readily applied to comparative biochemical research. Understanding and defining how proteins interact is one of the key aspects towards understanding how the proteome functions. To date, reductionist peptide-based research has helped to address a wide range of proteome-related research questions, including the prediction of enzymes substrates, identification of posttranslational modifications, and the annotation of protein interaction partners. Peptide arrays have been used to identify the binding specificity of reader domains, which are able to recognise the posttranslational modifications; forming dynamic protein interactions that are dependent on modification state. Finally, representing one of the fastest growing classes of inhibitor molecules, peptides are now begin explored as "disruptors" of protein-protein interactions or enzyme activity. Collectively, this review will discuss the use of peptides, peptide arrays, peptide-oriented computational biochemistry as modern reductionist strategies in deconvoluting the functional proteome.
    MeSH term(s) Animals ; Humans ; Peptide Fragments/chemistry ; Peptide Fragments/metabolism ; Protein Interaction Maps ; Protein Processing, Post-Translational ; Proteins/chemistry ; Proteins/metabolism ; Proteome/metabolism
    Chemical Substances Peptide Fragments ; Proteins ; Proteome
    Language English
    Publishing date 2021-05-15
    Publishing country England
    Document type Journal Article
    ZDB-ID 121247-3
    ISSN 1879-1107 ; 0305-0491 ; 1096-4959
    ISSN (online) 1879-1107
    ISSN 0305-0491 ; 1096-4959
    DOI 10.1016/j.cbpb.2021.110616
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Insights into a Cancer-Target Demethylase: Substrate Prediction through Systematic Specificity Analysis for KDM3A.

    Chopra, Anand / Willmore, William G / Biggar, Kyle K

    Biomolecules

    2022  Volume 12, Issue 5

    Abstract: Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the removal of methyl (- ... ...

    Abstract Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the removal of methyl (-CH
    MeSH term(s) Demethylation ; Histones/metabolism ; Humans ; Jumonji Domain-Containing Histone Demethylases ; Lysine ; Neoplasms ; Protein Processing, Post-Translational
    Chemical Substances Histones ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; KDM3A protein, human (EC 1.14.11.-) ; KDM6B protein, human (EC 1.14.11.-) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2022-04-27
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2701262-1
    ISSN 2218-273X ; 2218-273X
    ISSN (online) 2218-273X
    ISSN 2218-273X
    DOI 10.3390/biom12050641
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Unraveling the battle for lysine: A review of the competition among post-translational modifications.

    Shukri, Ali H / Lukinović, Valentina / Charih, François / Biggar, Kyle K

    Biochimica et biophysica acta. Gene regulatory mechanisms

    2023  Volume 1866, Issue 4, Page(s) 194990

    Abstract: Proteins play a critical role as key regulators in various biological systems, influencing crucial processes such as gene expression, cell cycle progression, and cellular proliferation. However, the functions of proteins can be further modified through ... ...

    Abstract Proteins play a critical role as key regulators in various biological systems, influencing crucial processes such as gene expression, cell cycle progression, and cellular proliferation. However, the functions of proteins can be further modified through post-translational modifications (PTMs), which expand their roles and contribute to disease progression when dysregulated. In this review, we delve into the methodologies employed for the characterization of PTMs, shedding light on the techniques and tools utilized to help unravel their complexity. Furthermore, we explore the prevalence of crosstalk and competition that occurs between different types of PTMs, specifically focusing on both histone and non-histone proteins. The intricate interplay between different modifications adds an additional layer of regulation to protein function and cellular processes. To gain insights into the competition for lysine residues among various modifications, computational systems such as MethylSight have been developed, allowing for a comprehensive analysis of the modification landscape. Additionally, we provide an overview of the exciting developments in the field of inhibitors or drugs targeting PTMs, highlighting their potential in combatting prevalent diseases. The discovery and development of drugs that modulate PTMs present promising avenues for therapeutic interventions, offering new strategies to address complex diseases. As research progresses in this rapidly evolving field, we anticipate remarkable advancements in our understanding of PTMs and their roles in health and disease, ultimately paving the way for innovative treatment approaches.
    MeSH term(s) Lysine/metabolism ; Acetylation ; Protein Processing, Post-Translational ; Histones/metabolism
    Chemical Substances Lysine (K3Z4F929H6) ; Histones
    Language English
    Publishing date 2023-09-24
    Publishing country Netherlands
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2918786-2
    ISSN 1876-4320 ; 1874-9399
    ISSN (online) 1876-4320
    ISSN 1874-9399
    DOI 10.1016/j.bbagrm.2023.194990
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: PeSA 2.0: A software tool for peptide specificity analysis implementing positive and negative motifs and motif-based peptide scoring.

    Topcu, Emine / Ridgeway, Nashira H / Biggar, Kyle K

    Computational biology and chemistry

    2022  Volume 101, Page(s) 107753

    Abstract: There are a vast number of molecular interactions that occur at the cellular level. Among these molecular interactions, interactions between multiple proteins are a widely studied area of research due to the importance of these interactions in cellular ... ...

    Abstract There are a vast number of molecular interactions that occur at the cellular level. Among these molecular interactions, interactions between multiple proteins are a widely studied area of research due to the importance of these interactions in cellular function and their potential in drug development. PeSA is a desktop application developed to facilitate the in vitro peptide study analysis to predict protein-protein interactions. PeSA can effortlessly generate visual outputs like motifs, bar charts, and visual matrices. Our implementation of PeSA version 2.0 includes additional tools, including the ability to further score peptide lists for consensus amongst interactions. The software is also able to design de novo peptides based on sequence motifs (sequence generator), which can be used to help design additional experiments for motif validation. Further, the efficacy of the sequence generator was validated using the lysine methyltransferase, SETD8, to identify new substrates of methylation based on motif-based predictions developed using PeSA2.0.
    MeSH term(s) Amino Acid Motifs ; Software ; Peptides/chemistry ; Proteins/chemistry ; Protein Processing, Post-Translational
    Chemical Substances Peptides ; Proteins
    Language English
    Publishing date 2022-08-13
    Publishing country England
    Document type Journal Article
    ISSN 1476-928X
    ISSN (online) 1476-928X
    DOI 10.1016/j.compbiolchem.2022.107753
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Characterization of KDM5 lysine demethylase family substrate preference and identification of novel substrates.

    Hoekstra, Matthew / Ridgeway, Nashira H / Biggar, Kyle K

    Journal of biochemistry

    2022  

    Abstract: The KDM5/JARID1 sub-family are 2-oxoglutarate and Fe(II)-dependent lysine-specific histone demethylases that are characterized by their Jumonji catalytic domains. The KDM5 family is known to remove tri-/di-methyl modifications from lysine-4 of histone H3 ...

    Abstract The KDM5/JARID1 sub-family are 2-oxoglutarate and Fe(II)-dependent lysine-specific histone demethylases that are characterized by their Jumonji catalytic domains. The KDM5 family is known to remove tri-/di-methyl modifications from lysine-4 of histone H3 (i.e., H3-K4me2/3), a mark associated with active gene expression. As a result, studies to date have revolved around the influence of KDM5 on disease through their ability to regulate H3-K4me2/3. Recent evidence demonstrates that KDM5 may influence disease beyond H3-K4 demethylation, making it critical to further investigate KDM5-mediated demethylation of non-histone proteins. To help identify potential non-histone substrates for the KDM5 family, we developed a library of 180 permutated peptide substrates (PPS), with sequences that are systematically altered from the wild-type H3-K4me3 substrate. From this library, we characterized recombinant KDM5A/B/C/D substrate preference and developed recognition motifs for each KDM5 demethylase. The recognition motifs developed were used to predict potential substrates for KDM5A/B/C/D and profiled to generate a list of high-ranking and medium/low-ranking substrates for further in vitro validation. Through this approach, we identified 66 high-ranking substrates in which KDM5 demethylases displayed significant in vitro activity towards.
    Language English
    Publishing date 2022-10-07
    Publishing country England
    Document type Journal Article
    ZDB-ID 218073-x
    ISSN 1756-2651 ; 0021-924X
    ISSN (online) 1756-2651
    ISSN 0021-924X
    DOI 10.1093/jb/mvac081
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Assessing sequence-based protein-protein interaction predictors for use in therapeutic peptide engineering.

    Charih, François / Biggar, Kyle K / Green, James R

    Scientific reports

    2022  Volume 12, Issue 1, Page(s) 9610

    Abstract: Engineering peptides to achieve a desired therapeutic effect through the inhibition of a specific target activity or protein interaction is a non-trivial task. Few of the existing in silico peptide design algorithms generate target-specific peptides. ... ...

    Abstract Engineering peptides to achieve a desired therapeutic effect through the inhibition of a specific target activity or protein interaction is a non-trivial task. Few of the existing in silico peptide design algorithms generate target-specific peptides. Instead, many methods produce peptides that achieve a desired effect through an unknown mechanism. In contrast with resource-intensive high-throughput experiments, in silico screening is a cost-effective alternative that can prune the space of candidates when engineering target-specific peptides. Using a set of FDA-approved peptides we curated specifically for this task, we assess the applicability of several sequence-based protein-protein interaction predictors as a screening tool within the context of peptide therapeutic engineering. We show that similarity-based protein-protein interaction predictors are more suitable for this purpose than the state-of-the-art deep learning methods publicly available at the time of writing. We also show that this approach is mostly useful when designing new peptides against targets for which naturally-occurring interactors are already known, and that deploying it for de novo peptide engineering tasks may require gathering additional target-specific training data. Taken together, this work offers evidence that supports the use of similarity-based protein-protein interaction predictors for peptide therapeutic engineering, especially peptide analogs.
    MeSH term(s) Algorithms ; Peptides/metabolism ; Peptides/therapeutic use
    Chemical Substances Peptides
    Language English
    Publishing date 2022-06-10
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-022-13227-9
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Evaluation of Jumonji C lysine demethylase substrate preference to guide identification of

    Hoekstra, Matthew / Chopra, Anand / Willmore, William G / Biggar, Kyle K

    STAR protocols

    2022  Volume 3, Issue 2, Page(s) 101271

    Abstract: Within the realm of lysine methylation, the discovery of lysine methyltransferase (KMTs) substrates has been burgeoning because of established systematic substrate screening protocols. Here, we describe a protocol enabling the systematic identification ... ...

    Abstract Within the realm of lysine methylation, the discovery of lysine methyltransferase (KMTs) substrates has been burgeoning because of established systematic substrate screening protocols. Here, we describe a protocol enabling the systematic identification of JmjC KDM substrate preference and
    MeSH term(s) Histones/metabolism ; Jumonji Domain-Containing Histone Demethylases/chemistry ; Lysine/chemistry ; Methylation
    Chemical Substances Histones ; Jumonji Domain-Containing Histone Demethylases (EC 1.14.11.-) ; Lysine (K3Z4F929H6)
    Language English
    Publishing date 2022-03-30
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 2666-1667
    ISSN (online) 2666-1667
    DOI 10.1016/j.xpro.2022.101271
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Assessing sequence-based protein–protein interaction predictors for use in therapeutic peptide engineering

    François Charih / Kyle K. Biggar / James R. Green

    Scientific Reports, Vol 12, Iss 1, Pp 1-

    2022  Volume 13

    Abstract: Abstract Engineering peptides to achieve a desired therapeutic effect through the inhibition of a specific target activity or protein interaction is a non-trivial task. Few of the existing in silico peptide design algorithms generate target-specific ... ...

    Abstract Abstract Engineering peptides to achieve a desired therapeutic effect through the inhibition of a specific target activity or protein interaction is a non-trivial task. Few of the existing in silico peptide design algorithms generate target-specific peptides. Instead, many methods produce peptides that achieve a desired effect through an unknown mechanism. In contrast with resource-intensive high-throughput experiments, in silico screening is a cost-effective alternative that can prune the space of candidates when engineering target-specific peptides. Using a set of FDA-approved peptides we curated specifically for this task, we assess the applicability of several sequence-based protein–protein interaction predictors as a screening tool within the context of peptide therapeutic engineering. We show that similarity-based protein–protein interaction predictors are more suitable for this purpose than the state-of-the-art deep learning methods publicly available at the time of writing. We also show that this approach is mostly useful when designing new peptides against targets for which naturally-occurring interactors are already known, and that deploying it for de novo peptide engineering tasks may require gathering additional target-specific training data. Taken together, this work offers evidence that supports the use of similarity-based protein–protein interaction predictors for peptide therapeutic engineering, especially peptide analogs.
    Keywords Medicine ; R ; Science ; Q
    Subject code 540
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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