ChemInform Abstract: AApeptides as a New Class of Peptidomimetics to Regulate Protein-Protein Interactions

AbstractAndrogen signaling through the androgen receptor (AR) directs gene expression in both normal and prostate cancer cells. Androgen regulates multiple aspects of the AR life cycle, including its localization and post-translational modification, but understanding how modifications are read and integrated with AR activity has been difficult. Here, we show that ADP-ribosylation regulates AR through a nuclear pathway mediated by Parp7. We show that Parp7 mono-ADP-ribosylates agonist-bound AR, and that ADP-ribosyl-cysteines within the N-terminal domain mediate recruitment of the E3 ligase Dtx3L/Parp9. Molecular recognition of ADP-ribosyl-cysteine is provided by tandem macrodomains in Parp9, and Dtx3L/Parp9 modulates expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of an androgen signaling axis that uses a writer and reader of ADP-ribosylation to regulate protein-protein interactions and AR activity.

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The Role of Posttranslational Modifications in DNA Repair

BioMed Research International ◽

10.1155/2020/7493902 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Miaomiao Bai ◽

Dongdong Ti ◽

Qian Mei ◽

Jiejie Liu ◽

Xin Yan ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Protein Interactions ◽

Posttranslational Modifications ◽

Genome Stability ◽

Protein Localization ◽

Complex Structure ◽

Protein Protein Interactions ◽

Regulate Protein

The human body is a complex structure of cells, which are exposed to many types of stress. Cells must utilize various mechanisms to protect their DNA from damage caused by metabolic and external sources to maintain genomic integrity and homeostasis and to prevent the development of cancer. DNA damage inevitably occurs regardless of physiological or abnormal conditions. In response to DNA damage, signaling pathways are activated to repair the damaged DNA or to induce cell apoptosis. During the process, posttranslational modifications (PTMs) can be used to modulate enzymatic activities and regulate protein stability, protein localization, and protein-protein interactions. Thus, PTMs in DNA repair should be studied. In this review, we will focus on the current understanding of the phosphorylation, poly(ADP-ribosyl)ation, ubiquitination, SUMOylation, acetylation, and methylation of six typical PTMs and summarize PTMs of the key proteins in DNA repair, providing important insight into the role of PTMs in the maintenance of genome stability and contributing to reveal new and selective therapeutic approaches to target cancers.

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Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer

Biochemical Society Transactions ◽

10.1042/bst20210749 ◽

2021 ◽

Author(s):

Erinna F. Lee ◽

W. Douglas Fairlie

Keyword(s):

Structural Biology ◽

Protein Interactions ◽

Basic Science ◽

Great Success ◽

Protein Protein Interactions ◽

New Class ◽

Success Stories ◽

History Of ◽

Approved Drugs ◽

Close Relatives

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

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Multivalent peptides displayed on OEGMA-based copolymers for the modulation of protein–protein interactions

Polymer Chemistry ◽

10.1039/c5py01080b ◽

2015 ◽

Vol 6 (45) ◽

pp. 7862-7870 ◽

Cited By ~ 1

Author(s):

Yujie Li ◽

Tao Li ◽

Jinghui Wang ◽

Xiaojia Bao ◽

Yibing Zhao ◽

...

Keyword(s):

Protein Interactions ◽

Protein Protein Interactions ◽

Peptide Conjugates ◽

New Class ◽

Multiple Copies

We report a new class of copolymer–peptide conjugates which exploits the comb-shaped pOEGMA as a polymeric backbone, into which multiple copies of peptide chains that can modulate intracellular p53–Mdm2 or p53–Mdm4 protein interactions are incorporated.

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Genetically encoded selective cross-linkers and emerging applications

Biochemical Society Transactions ◽

10.1042/bst20200508 ◽

2020 ◽

Vol 48 (4) ◽

pp. 1807-1817

Author(s):

Haiyan Ren

Keyword(s):

Protein Interactions ◽

Unnatural Amino Acids ◽

Protein Complexes ◽

Living Cells ◽

Cross Linking ◽

Protein Protein Interactions ◽

New Class ◽

Selective Reaction ◽

Biological Studies ◽

Lower Background

There has been a large amount of interest in the development of genetically encoded cross-linkers that target functional groups naturally present in cells. Recently, a new class of unnatural amino acids that specifically react with target residues were developed and genetically incorporated. The selective reaction shows higher cross-linking efficiency, lower background and predictable cross-linking sites. It has been applied to enhance protein/peptide stability, pinpoint protein–protein interactions, stabilize protein complexes, engineer covalent protein inhibitors, identify phosphatases in living cells, etc. These new covalent linkages provide excellent new tools for protein engineering and biological studies. Their applications in biotherapy will provide considerable opportunities for innovating and improving biomolecular medicines.

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Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

Molecules ◽

10.3390/molecules25153509 ◽

2020 ◽

Vol 25 (15) ◽

pp. 3509

Author(s):

Matteo Mori ◽

Ettore Gilardoni ◽

Luca Regazzoni ◽

Alessandro Pedretti ◽

Diego Colombo ◽

...

Keyword(s):

Protein Interactions ◽

Malignant Tumors ◽

Uv Spectroscopy ◽

Sh2 Domain ◽

Significant Activity ◽

Protein Protein Interactions ◽

New Class ◽

Mechanism Of Interaction ◽

The Relationship ◽

Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.

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The Function of FEN1 is Regulated by Post-Translational Modification

10.5772/intechopen.96635 ◽

2021 ◽

Author(s):

Zhenxing Wu ◽

Xiaofen Mo ◽

Chengbo Lang ◽

Jinjing Luo

Keyword(s):

Protein Interactions ◽

Cellular Localization ◽

Genome Instability ◽

Nuclease Activity ◽

Protein Protein Interactions ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Dna Structures ◽

Effective Role ◽

Regulate Protein

Flap endonuclease 1 (FEN1) is a multifunctional DNA branching nuclease. Post-translational modifications (PTMs) exist in this protein widely, including phosphorylation, methylation, acetylation, ubiquitination and small ubiquitination modification (SUMO). Here, we make a summary for those PTMs studies on FEN1, to illustrate relationships between mutations of those amino acids and their functions alteration of FEN1. Numerous evidences have confirmed that dysfunction of FEN1 would lead to genome instability, and then induce a variety of chromosome-related diseases ultimately, including tumors. On one hand, interaction partner also stimulates FEN1 nuclease activity, to further ensure an effective role in the processing of different DNA structures; on the other hand, PTMs may regulate protein-protein interactions and FEN1’s cellular localization.

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Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

10.26434/chemrxiv.13017845 ◽

2020 ◽

Author(s):

Tomoki Himiyama ◽

Yuko Tsuchiya ◽

Yasushige Yonezawa ◽

Tsutomu Nakamura

Keyword(s):

Amino Acid ◽

Protein Interactions ◽

Hot Spots ◽

Quaternary Structure ◽

Protein Assembly ◽

Protein Protein Interactions ◽

Aeropyrum Pernix ◽

Amino Acid Mutations ◽

Regulate Protein ◽

Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

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Arginine Methylation of the ICP27 RGG Box Regulates the Functional Interactions of ICP27 with SRPK1 and Aly/REF during Herpes Simplex Virus 1 Infection

Journal of Virology ◽

10.1128/jvi.00801-09 ◽

2009 ◽

Vol 83 (17) ◽

pp. 8970-8975 ◽

Cited By ~ 21

Author(s):

Stuart K. Souki ◽

Rozanne M. Sandri-Goldin

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Protein Interactions ◽

Arginine Methylation ◽

Protein Protein Interactions ◽

Herpes Simplex Virus 1 ◽

Methylation Inhibitor ◽

Arginine Residues ◽

Regulate Protein ◽

Simplex Virus

ABSTRACT The herpes simplex virus 1 protein ICP27 is methylated on arginine residues within an RGG box, and arginine methylation regulates ICP27 export to the cytoplasm. Arginine methylation can regulate protein-protein interactions; therefore, we examined the effect of hypomethylation on ICP27's interactions with cellular proteins SRPK1 and Aly/REF, which bind to ICP27 through the RGG box region. During infections with viral mutants containing lysine substitutions or the methylation inhibitor adenosine dialdehyde, the interaction of ICP27 with SRPK1 and Aly/REF was decreased, as determined by coimmunoprecipitation and colocalization studies, indicating that ICP27 RGG box methylation regulates interaction with these proteins.

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