Proteolysis targeting chimera (PROTAC) is a state‐of‐the‐art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril‐based PROTAC strategy to form a polynary (E3)m : PROTAC : (POI)ncomplex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self‐assembly‐driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so‐called Nano‐PROTAC provides a novel approach for TPD in cancer therapy.
- Award ID(s):
- 1761320
- NSF-PAR ID:
- 10370111
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Date Published:
- Journal Name:
- Nature Communications
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2041-1723
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract -
Abstract Proteolysis targeting chimera (PROTAC) is a state‐of‐the‐art technology for ablating undruggable targets. A PROTAC degrader achieves targeted protein degradation (TPD) through the simultaneous binding of a protein of interest (POI) and an E3 ligase to form a ternary complex. A nanofibril‐based PROTAC strategy to form a polynary (E3)m : PROTAC : (POI)ncomplex has not been reported in the TPD field up to this point. A recent innovation shows that a POI ligand and E3 ligase ligand don't have to be within a fused degrader molecule. Instead, they can be recruited to cellular proximity by a self‐assembly‐driving peptide and click chemistry. The resulting nanofibrils can recruit multiple POI and E3 ligase molecules to form a polynary complex as a degradation center. The so‐called Nano‐PROTAC provides a novel approach for TPD in cancer therapy.
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Summary Light signal provides the spatial and temporal information for plants to adapt to the prevailing environmental conditions. Alterations in light quality and quantity can trigger robust changes in global gene expression. In
Arabidopsis thaliana , two groups of key factors regulating those changes in gene expression areCONSTITUTIVE PHOTOMORPHOGENESIS /DEETIOLATED /FUSCA (COP /DET /FUS ) and a subset of basic helix‐loop‐helix transcription factors calledPHYTOCHROME ‐INTERACTING FACTORS (PIF s). Recently, rapid progress has been made in characterizing the E3 ubiquitin ligases for the light‐induced degradation ofPIF 1,PIF 3 andPIF 4; however, the E3 ligase(s) forPIF 5 remains unknown. Here, we show that theCUL 4COP 1–SPA complex is necessary for the red light‐induced degradation ofPIF 5. Furthermore,COP 1 andSPA proteins stabilizePIF 5 in the dark, but promote the ubiquitination and degradation ofPIF 5 in response to red light through the 26S proteasome pathway. Genetic analysis illustrates that overexpression of can partially suppress bothPIF 5cop1‐4 andspaQ seedling de‐etiolation phenotypes under dark and red‐light conditions. In addition, thePIF 5 protein level cycles under both diurnal and constant light conditions, which is also defective in thecop1‐4 andspaQ backgrounds. Bothcop1‐4 andspaQ show defects in diurnal growth pattern. Overexpression of partially restores growth defects inPIF 5cop1‐4 andspaQ under diurnal conditions, suggesting that theCOP 1–SPA complex plays an essential role in photoperiodic hypocotyl growth, partly through regulating thePIF 5 level. Taken together, our data illustrate how theCUL 4COP 1–SPA E3 ligase dynamically controls thePIF 5 level to regulate plant development. -
Protein degradation through the Ubiquitin (Ub)-26S Proteasome System (UPS) is a major gene expression regulatory pathway in plants. In this pathway, the 76-amino acid Ub proteins are covalently linked onto a large array of UPS substrates with the help of three enzymes (E1 activating, E2 conjugating, and E3 ligating enzymes) and direct them for turnover in the 26S proteasome complex. The S-phase Kinase-associated Protein 1 (Skp1), CUL1, F-box (FBX) protein (SCF) complexes have been identified as the largest E3 ligase group in plants due to the dramatic number expansion of the FBX genes in plant genomes. Since it is the FBX proteins that recognize and determine the specificity of SCF substrates, much effort has been done to characterize their genomic, physiological, and biochemical roles in the past two decades of functional genomic studies. However, the sheer size and high sequence diversity of the FBX gene family demands new approaches to uncover unknown functions. In this work, we first identified 82 known FBX members that have been functionally characterized up to date in Arabidopsis thaliana . Through comparing the genomic structure, evolutionary selection, expression patterns, domain compositions, and functional activities between known and unknown FBX gene members, we developed a neural network machine learning approach to predict whether an unknown FBX member is likely functionally active in Arabidopsis, thereby facilitating its future functional characterization.more » « less
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Abstract Most members of basic leucine zipper (bZIP) transcription factor (TF) subgroup A play important roles as positive effectors in abscisic acid (ABA) signaling during germination and/or in vegetative stress responses. In multiple plant species, one member, ABA insensitive 5 (ABI5), is a major TF that promotes seed maturation and blocks early seeding growth in response to ABA. Other members, referred to as either ABRE‐binding factors (ABFs), ABRE‐binding proteins (AREBs), or D3 protein‐binding factors (DPBFs), are implicated as major players in stress responses during vegetative growth. Studies on the proteolytic regulation of ABI5, ABF1, and ABF3 in
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