Shedding light on complexity of protein–protein interactions in cancer

Yoon, Tae–Young; Lee, Hong-Won

doi:10.1016/j.cbpa.2019.07.001

Cited by 7 publications

(6 citation statements)

References 53 publications

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“…Identifying unique targets of TP53 mutants that do not bind to wild type TP53 could open pathways to new drug targets up and downstream, offering unique therapeutic opportunities to treat cancer. 68,69 In conclusion, we overlayed protein fragment interaction pairs with known protein contact points from a recent cryo-EM structure of the MCM complex allowing us to obtain a high resolution view of the interacting domains. We show the intrinsically disordered wild type TP53 interacts with MCM2, MCM3, and MCM5.…”

Section: Discussionmentioning

confidence: 99%

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Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5

et al. 2022

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Objective Identify protein contact points between TP53 and minichromosome maintenance (MCM) complex proteins 2, 3, and 5 with high resolution allowing for potential novel Cancer drug design. Methods A next‐generation sequencing‐based protein–protein interaction method developed in our laboratory called AVA‐Seq was applied to a gold‐standard human protein interaction set. Proteins including TP53, MCM2, MCM3, MCM5, HSP90AA1, PCNA, NOD1, and others were sheared and ligated into the AVA‐Seq system. Protein–protein interactions were then identified in both mild and stringent selective conditions. Results Known interactions among MCM2, MCM3, and MCM5 were identified with the AVA‐Seq system. The interacting regions detected between these three proteins overlap with the structural data of the MCM complex, and novel domains were identified with high resolution determined by multiple overlapping fragments. Fragments of wild type TP53 were shown to interact with MCM2, MCM3, and MCM5, and details on the location of the interactions were provided. Finally, a mini‐network of known and novel cancer protein interactions was provided, which could have implications for fundamental changes in multiple cancers. Conclusion We provide a high‐resolution mini‐interactome that could direct novel drug targets and implicate possible effects of specific cancer mutations.

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Section: Discussionmentioning

confidence: 99%

“…This would be advantageous because targeted inhibition of a particular cancer mutation would have minimal effect on normal cells. Identifying unique targets of TP53 mutants that do not bind to wild type TP53 could open pathways to new drug targets up and downstream, offering unique therapeutic opportunities to treat cancer 68,69 …”

Section: Discussionmentioning

confidence: 99%

Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5

et al. 2022

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“…Co-IP is a classical and efficient method to study protein interactions based on the specific interaction between antibodies and antigens, 6 an appropriate Co-IP system requires highly specific antibodies to target proteins. To verify interactions of new cross-links identified by APEX-CXMS, plasmids containing selected targeting proteins fused with Flag-tag and Myc-tag were constructed and transiently transfected into HEK293T cells.…”

Section: Apex-cxms For Profiling Mitochondrial Protein− Protein Inter...mentioning

confidence: 99%

“…1 Several techniques have been developed to study binary protein−protein interactions, including the yeast two-hybrid (Y2H) system, 2 fluorescence resonance energy transfer (FRET), 3 and protein-fragment complementation assay (PCA). 4 Affinity purification mass spectrometry (AP-MS) 5 and co-immunoprecipitation (Co-IP) 6 prefer to detect interactions among protein complexes. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) 7 are especially suitable for detecting interactions between purified proteins.…”

Section: ■ Introductionmentioning

confidence: 99%

Subcellular Interactomes Revealed by Merging APEX with Cross-Linking Mass Spectrometry

et al. 2022

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Subcellular protein−protein interactions (PPIs) are essential to understanding the mechanism of diverse cellular signaling events and the pathogenesis of diseases. Herein, we report an integrated APEX proximity labeling and chemical crosslinking coupled with mass spectrometry (CXMS) platform named APEX-CXMS for spatially resolved subcellular interactome profiling in a high-throughput manner. APEX proximity labeling rapidly captures subcellular proteomes, and the highly reactive chemical cross-linkers can capture weak and dynamic interactions globally without extra genetic manipulation. APEX-CXMS was first applied to mitochondria and identified 653 pairs of interprotein cross-links. Six pairs of new interactions were selected and verified by coimmunoprecipitation, the mammalian two-hybrid system, and surface plasmon resonance method. Besides, our approach was further applied to the nucleus, capturing 336 pairs of interprotein cross-links with approximately 94% nuclear specificity. APEX-CXMS thus provides a simple, fast, and general alternative to map diverse subcellular PPIs.

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“…Perturbed PPIs in cancer (cancer-specific PPIs) is one of the key factors in cancer development [ 39 ]. Mapping PPIs has provided invaluable insights into the pathophysiological mechanisms in multiple types of cancer [ 40 ]. Moreover, aberrant PPIs are arising as new targets for the development of novel cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

Xie

Jiang

2022

Cancers

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The dynamic O-GlcNAc modification of intracellular proteins is an important nutrient sensor for integrating metabolic signals into vast networks of highly coordinated cellular activities. Dysregulation of the sole enzymes responsible for O-GlcNAc cycling, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), and the associated cellular O-GlcNAc profile is a common feature across nearly every cancer type. Many studies have investigated the effects of aberrant OGT/OGA expression on global O-GlcNAcylation activity in cancer cells. However, recent studies have begun to elucidate the roles of protein–protein interactions (PPIs), potentially through regions outside of the immediate catalytic site of OGT/OGA, that regulate greater protein networks to facilitate substrate-specific modification, protein translocalization, and the assembly of larger biomolecular complexes. Perturbation of OGT/OGA PPI networks makes profound changes in the cell and may directly contribute to cancer malignancies. Herein, we highlight recent studies on the structural features of OGT and OGA, as well as the emerging roles and molecular mechanisms of their aberrant PPIs in rewiring cancer networks. By integrating complementary approaches, the research in this area will aid in the identification of key protein contacts and functional modules derived from OGT/OGA that drive oncogenesis and will illuminate new directions for anti-cancer drug development.

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Shedding light on complexity of protein–protein interactions in cancer

Cited by 7 publications

References 53 publications

Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5

Novel protein contact points among TP53 and minichromosome maintenance complex proteins 2, 3, and 5

Subcellular Interactomes Revealed by Merging APEX with Cross-Linking Mass Spectrometry

The Emerging Roles of Protein Interactions with O-GlcNAc Cycling Enzymes in Cancer

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