المؤلفون: Meidan Ying, Xuejing Shao, Hong Zhu, Ji Cao, Bo Yang, Yifan Chen, Qiaojun He

المصدر: Acta Pharmaceutica Sinica B, Vol 11, Iss 2, Pp 309-321 (2021)
Acta Pharmaceutica Sinica. B

مصطلحات موضوعية: SRC-3, nuclear receptor coactivator 3, VHL, von Hippel-Lindau tumor suppressor, RRM2, ribonucleotide reductase regulatory subunit M2, KRAS, KRAS proto-oncogene, GTPase, SNAIL1, snail family transcriptional repressor 1, medicine.medical_treatment, CRL, cullin-RING ligase, ERK, mitogen-activated protein kinase 1, NEDD8, NEDD8 ubiquitin like modifier, Review, medicine.disease_cause, JAB1, c-Jun activation domain binding protein-1, p130Cas, BCAR1 scaffold protein, Cas family member, law.invention, Targeted therapy, Degradation, 0302 clinical medicine, Ubiquitin, law, RA, retinoic acid, FBXL3, F-box and leucine rich repeat protein, Ci, cubitus interruptus, Phosphorylation, General Pharmacology, Toxicology and Pharmaceutics, Crosstalk, FBXO3/31, F-box protein 3/31, 0303 health sciences, biology, KEAP1, kelch like ECH associated protein 1, Kinase, Chemistry, KBTBD8, kelch repeat and BTB domain containing 8, CSN, COP9 signalosome, DYRK1A/B, dual-specificity tyrosine-phosphorylation-regulated kinases 1A/B, FBW7, F-box and WD repeat domain containing 7, CDT2, denticleless E3 ubiquitin protein ligase homolog, NRF2, nuclear factor, erythroid 2 like 2, TCN, triciribine hydrate, Cell biology, USP37, ubiquitin specific peptidase 37, Crosstalk (biology), XBP1, X-box binding protein 1, 030220 oncology & carcinogenesis, HCC, hepatocellular carcinomas, Vps34, phosphatidylinositol 3-kinase catalytic subunit type 3, CK1/2, casein kinase I/II, COMMD1, copper metabolism domain containing 1, KLHL3, kelch like family member 3, EMT, epithelial–mesenchymal transition, Cullin, P-TEFb, positive transcription elongation factor b, CDK2/4, cyclin dependent kinase 2/4, SPOP, speckle-type POZ protein, AIRE, autoimmune regulator, PYGO2, pygopus 2, TCOF1, treacle ribosome biogenesis factor 1, ID2, inhibitor of DNA binding 2, CHK1, checkpoint kinase 1, Kinases, FZR1, fizzy and cell division cycle 20 related 1, HIF1α, NF-κB and hypoxia inducible factor 1 subunit alpha, EXO1, exonuclease 1, ZBTB16, zinc finger and BTB domain containing 16, NOLC1, nucleolar and coiled-body phosphoprotein 1, 03 medical and health sciences, PKM2, pyruvate kinase M2 isoform, KDM2B, lysine demethylase 2B, PKC, protein kinase C, Cullin-RING ligases, medicine, BMAL1, aryl hydrocarbon receptor nuclear translocator like, ATR, ataxia telangiectasia-mutated and Rad3-related, SOCS6, suppressor of cytokine signaling 6, 030304 developmental biology, PDL1, programmed death ligand 1, HIB, Hedghog-induced MATH and BTB domain-containing protein, AKT, AKT serine/threonine kinase, lcsh:RM1-950, Ubiquitination, TRF1, telomeric repeat binding factor 1, DDB1, damage specific DNA binding protein 1, BCL2, BCL2 apoptosis regulator, CLOCK, clock circadian regulator, MYC, MYC proto-oncogene, bHLH transcription factor, lcsh:Therapeutics. Pharmacology, c-Fos, Fos proto-oncogene, AP-1 transcription factor subunit, RARα, RA receptor α, Tumorigenesis, biology.protein, Suppressor, CRY1, cryptochrome circadian regulator 1, ERG, ETS transcription factor ERG, Carcinogenesis

الوصف: Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.
Graphical abstract This review summarizes the crosstalk between phosphorylation and ubiquitination in different biological processes and diseases, mainly cancers, and highlights the therapeutic potential of the crosstalk in tumor treatments.Image 1

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f27b7f488f3a53677836e1b8e5b2722dTest
https://doi.org/10.1016/j.apsb.2020.09.007Test

المؤلفون: Amie K. Boal, Scott A. Showalter, Nafiseh Sabri, Roman Rohac, Emery T. Usher, Tanja Mittag

المصدر: The Journal of Biological Chemistry

مصطلحات موضوعية: 0301 basic medicine, Models, Molecular, endocrine system diseases, SBM1, SB motif 1, Amino Acid Motifs, SPOP, Biochemistry, IDRs, intrinsically disordered regions, PBST, Triton X-100 in PBS, Ubiquitin, Pdx1, biology, diabetes, FA, fluorescence anisotropy, Nuclear Proteins, Editors' Pick, multivalency, MATH, meprin and tumor necrosis factor receptor-associated factor homology, Ubiquitin ligase, Cell biology, LLPS, liquid–liquid phase separation, Protein Transport, Ni-NTA, nickel-nitrilotriacetic acid, PDX1, SBM2, SB motif 2, Protein Binding, Research Article, DAXX, death domain-associated protein 6, SPOP, speckle-type POZ protein, endocrine system, ubiquitination, digestive system, 03 medical and health sciences, Death-associated protein 6, Humans, structure, Molecular Biology, Transcription factor, Puc, puckered protein, Homeodomain Proteins, Nucleoplasm, 030102 biochemistry & molecular biology, Cell Biology, Repressor Proteins, 030104 developmental biology, SB, SPOP-binding, biology.protein, Trans-Activators, Homeobox, AR, androgen receptor, Pdx1, pancreatic and duodenal homeobox 1, DAPI, 4′,6-diamidino-2-phenylindole

الوصف: Speckle-type POZ protein (SPOP) is a ubiquitin ligase adaptor that binds substrate proteins and facilitates their proteasomal degradation. Most SPOP substrates present multiple SPOP-binding (SB) motifs and undergo liquid–liquid phase separation with SPOP. Pancreatic and duodenal homeobox 1 (Pdx1), an insulin transcription factor, is downregulated by interaction with SPOP. Unlike other substrates, only one SB motif has previously been reported within the Pdx1 C-terminal intrinsically disordered region (Pdx1-C). Given this difference, we aimed to determine the specific mode of interaction of Pdx1 with SPOP and how it is similar or different to that of other SPOP substrates. Here, we identify a second SB motif in Pdx1-C, but still find that the resulting moderate valency is insufficient to support phase separation with SPOP in cells. Although Pdx1 does not phase separate with SPOP, Pdx1 and SPOP interaction prompts SPOP relocalization from nuclear speckles to the diffuse nucleoplasm. Accordingly, we find that SPOP-mediated ubiquitination activity of Pdx1 occurs in the nucleoplasm and that highly efficient Pdx1 turnover requires both SB motifs. Our results suggest that the subnuclear localization of SPOP–substrate interactions and substrate ubiquitination may be directed by the properties of the substrate itself.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::865b2261c9773bb5532b2ebeb6469bacTest
https://pubmed.ncbi.nlm.nih.gov/33894201Test

المؤلفون: Gilbert G. Privé, Jihun Lee, Sophia A. Kenrick, Tanja Mittag, Michal Sharon, Peter Schuck, Melissa R. Marzahn, Suresh Marada, Huaying Zhao, Wesley J. Errington, Regina-Maria Kolaitis, Stacey K. Ogden, Gili Ben-Nissan, Stanley Pounds, Jennifer L. Peters, Amanda Nourse, J. Paul Taylor

المصدر: The EMBO Journal

مصطلحات موضوعية: 0301 basic medicine, Macromolecular Substances, membrane‐less organelle, speckle‐type POZ protein, Mutant, Kruppel-Like Transcription Factors, Nerve Tissue Proteins, SPOP, Oligomer, ubiquitin ligase, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, chemistry.chemical_compound, Ubiquitin, Protein Domains, Structural Biology, Zinc Finger Protein Gli3, Organelle, medicine, isodesmic self‐association, Humans, Molecular Biology, Cell Nucleus, 030102 biochemistry & molecular biology, General Immunology and Microbiology, biology, General Neuroscience, Ubiquitination, RNA, Post-translational Modifications, Proteolysis & Proteomics, Nuclear Proteins, Articles, Protein Biosynthesis & Quality Control, prostate cancer, Ubiquitin ligase, Repressor Proteins, 030104 developmental biology, medicine.anatomical_structure, chemistry, Biochemistry, biology.protein, Biophysics, Protein Multimerization, Nucleus, Protein Binding

الوصف: Membrane‐less organelles in cells are large, dynamic protein/protein or protein/RNA assemblies that have been reported in some cases to have liquid droplet properties. However, the molecular interactions underlying the recruitment of components are not well understood. Herein, we study how the ability to form higher‐order assemblies influences the recruitment of the speckle‐type POZ protein (SPOP) to nuclear speckles. SPOP, a cullin‐3‐RING ubiquitin ligase (CRL3) substrate adaptor, self‐associates into higher‐order oligomers; that is, the number of monomers in an oligomer is broadly distributed and can be large. While wild‐type SPOP localizes to liquid nuclear speckles, self‐association‐deficient SPOP mutants have a diffuse distribution in the nucleus. SPOP oligomerizes through its BTB and BACK domains. We show that BTB‐mediated SPOP dimers form linear oligomers via BACK domain dimerization, and we determine the concentration‐dependent populations of the resulting oligomeric species. Higher‐order oligomerization of SPOP stimulates CRL3 SPOP ubiquitination efficiency for its physiological substrate Gli3, suggesting that nuclear speckles are hotspots of ubiquitination. Dynamic, higher‐order protein self‐association may be a general mechanism to concentrate functional components in membrane‐less cellular bodies.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0d98ac140a585464c6be21774026e4b9Test
http://europepmc.org/articles/PMC4910529Test

المؤلفون: Christy R. Grace, Jihun Lee, Junmin Peng, Melissa R. Marzahn, Amanda Nourse, Tanja Mittag, Edmond R. Watson, Anthony A. High, Wendy K. Pierce, Brenda A. Schulman

المصدر: Journal of Molecular Biology. 428(6):1256-1271

مصطلحات موضوعية: 0301 basic medicine, Ubiquitin-Protein Ligases, Amino Acid Motifs, Plasma protein binding, SPOP, Article, 03 medical and health sciences, NMR spectroscopy, Ubiquitin, Structural Biology, cancer, Animals, Short linear motif, Speckle-type POZ protein, Molecular Biology, chemistry.chemical_classification, DNA ligase, biology, Ubiquitination, Processivity, multivalency, degron, Ubiquitin ligase, Cell biology, 030104 developmental biology, Biochemistry, chemistry, Hedgehogs, biology.protein, Degron, Protein Binding, Transcription Factors

الوصف: Primary sequence motifs, with millimolar affinities for binding partners, are abundant in disordered protein regions. In multivalent interactions, such weak linear motifs can cooperate to recruit binding partners via avidity effects. If linear motifs recruit modifying enzymes, optimal placement of weak motifs may regulate access to modification sites. Weak motifs may thus exert physiological relevance stronger than that suggested by their affinities, but molecular mechanisms of their function are still poorly understood. Herein, we use the N-terminal disordered region of the Hedgehog transcriptional regulator Gli3 (Gli31-90) to determine the role of weak motifs encoded in its primary sequence for the recruitment of its ubiquitin ligase CRL3SPOP and the subsequent effect on ubiquitination efficiency. The substrate adaptor SPOP binds linear motifs through its MATH (meprin and TRAF homology) domain and forms higher-order oligomers through its oligomerization domains, rendering SPOP multivalent for its substrates. Gli3 has multiple weak SPOP binding motifs. We map three such motifs in Gli31-90, the weakest of which has a millimolar dissociation constant. Multivalency of ligase and substrate for each other facilitates enhanced ligase recruitment and stimulates Gli31-90 ubiquitination in in vitro ubiquitination assays. We speculate that the weak motifs enable processivity through avidity effects and by providing steric access to lysine residues that are otherwise not prioritized for polyubiquitination. Weak motifs may generally be employed in multivalent systems to act as gatekeepers regulating post-translational modification.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::12958f008244d5d2c06bc515281da419Test

المؤلفون: Bulatov, Emil, Ciulli, Alessio

المصدر: Biochemical Journal

مصطلحات موضوعية: Models, Molecular, Skp2, S-phase kinase-associated protein 2, Fbxl, F-box/leucine-rich motif-containing protein, SCF, Skp1–Cdc53–F-box Cdc4, DDB, damage-specific DNA-binding protein, DCAF, DDB1–Cul4A-associated factor, EloBC, ElonginB–ElonginC complex, Review Article, SV5, simian virus 5, Nrf2, nuclear factor-erythroid 2-related factor 2, Vpr, viral protein R, JA-Ile, jasmonoyl-isoleucine, CRL, Cullin–RING E3 ubiquitin ligase, HERC2, HECT domain- and RLD (regulator of chromosome condensation 1 protein-like domain) domain-containing E3 ubiquitin protein ligase 2, BCR, BTB–Cul3–Rbx1, Drug Discovery, NAE, NEDD8-activating enzyme, KLHL, Kelch-like protein, Ub, ubiquitin, IκB, inhibitor of NF-κB, Vif, virion infectivity factor, Molecular Structure, ITC, isothermal titration calorimetry, CPH, conserved within Cul7, PARC and HERC2, Cpd, compound, Aux, auxin, Cullin Proteins, structure-based design, CTD, C-terminal domain, Protac, proteolysis-targeting chimaeric molecule, Cul, Cullin, Fbw/Fbxw, F-box/WD repeat-containing protein, STAT, signal transducer and activator of transcription, GHR, growth hormone receptor, UBL, ubiquitin-like protein, FP, fluorescence polarization, NF-κB, nuclear factor κB, Cks1, cyclin-dependent protein kinase regulatory subunit 1, Rbx1, RING-box protein 1, Proteasome Inhibitors, SH2, Src homology 2, assembly, SPOP, speckle-type POZ protein, UPS, ubiquitin–proteasome system, PARC, p53-associated parkin-like cytoplasmic protein, β-TrCP, β-transducin repeat-containing protein, PPI, protein–protein interaction, small molecule, JAZ1, jasmonate/ZIM (zinc finger expressed in inflorescence) domain protein 1, Fbxo, F-box/other domain-containing protein, mTOR, mammalian target of rapamycin, NEDD, neural-precursor-cell-expressed developmentally down-regulated, ubiquitination, APC/C, anaphase-promoting complex/cyclosome, MEL26, maternal effect lethal 26, RING, really interesting new gene, CAND1, Cullin-associated NEDD8-dissociated protein 1, Cdc, cell division cycle, ubiquitin, Ubc12, ubiquitin-conjugating enzyme 12, COI1, coronatine-insensitive protein 1, CSA, Cockayne syndrome A, Humans, structure, NTD, N-terminal domain, CRBN, cereblon, Protein Structure, Quaternary, SMER3, small-molecule enhancer of rapamycin 3, CSN, COP9 (constitutive photomorphogenesis 9) signalosome complex, CBFβ, core binding factor β, IAA, indole-3-acetic acid, SOCS, suppressor of cytokine signalling, BTB, bric-a-brac/tramtrack/broad complex, MATH, meprin and TRAF (tumour necrosis factor receptor-associated factor) homology, Keap1, Kelch-like enoyl-CoA hydratase-associated protein 1, Protein Structure, Tertiary, VHL, von Hippel–Lindau, Protein Subunits, ASB, ankyrin repeat and SOCS-box, BP, β-propeller, HECT, homologous with E6-associated protein C-terminus, Drug Design, HIF-1α, hypoxia-inducible factor 1α, VPRBP, Vpr-binding protein, TIR1, transport inhibitor response 1, POZ, pox virus and zinc finger

الوصف: In the last decade, the ubiquitin-proteasome system has emerged as a valid target for the development of novel therapeutics. E3 ubiquitin ligases are particularly attractive targets because they confer substrate specificity on the ubiquitin system. CRLs [Cullin-RING (really interesting new gene) E3 ubiquitin ligases] draw particular attention, being the largest family of E3s. The CRLs assemble into functional multisubunit complexes using a repertoire of substrate receptors, adaptors, Cullin scaffolds and RING-box proteins. Drug discovery targeting CRLs is growing in importance due to mounting evidence pointing to significant roles of these enzymes in diverse biological processes and human diseases, including cancer, where CRLs and their substrates often function as tumour suppressors or oncogenes. In the present review, we provide an account of the assembly and structure of CRL complexes, and outline the current state of the field in terms of available knowledge of small-molecule inhibitors and modulators of CRL activity. A comprehensive overview of the reported crystal structures of CRL subunits, components and full-size complexes, alone or with bound small molecules and substrate peptides, is included. This information is providing increasing opportunities to aid the rational structure-based design of chemical probes and potential small-molecule therapeutics targeting CRLs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid________::5b07715f4217b08830d90ae742dc138fTest
http://europepmc.org/articles/PMC4403949Test

المؤلفون: Canning, Peter, Bullock, Alex N.

المصدر: Biochemical Society Transactions

مصطلحات موضوعية: SPOP, speckle-type POZ protein, antioxidant response, drug design, BTB, broad complex/tramtrack/bric-à-brac, MATH, meprin and TRAF (tumour-necrosis-factor-receptor-associated factor) homology, Nrf2, nuclear factor erythroid 2-related factor 2, S5, Protein Structure, Secondary, Rbx, RING box protein, RING, really interesting new gene, cancer, Humans, ARE, antioxidant-response element, Molecular Targeted Therapy, ubiquitylation, Protein Structure, Quaternary, Biochemical Society Focused Meeting, degradation, Kelch-Like ECH-Associated Protein 1, KLHL, Kelch-like, BACK, BTB and C-terminal Kelch, Intracellular Signaling Peptides and Proteins, Ubiquitination, cell signalling, Cullin Proteins, Protein Structure, Tertiary, CRL, Cullin–RING ligase, HECT, homologous with E6-associated protein C-terminus, Multiprotein Complexes, KEAP1, Kelch-like ECH-associated protein 1, POZ, pox virus and zinc finger

الوصف: E3 ubiquitin ligases that direct substrate proteins to the ubiquitin-proteasome system are promising, though largely unexplored drug targets both because of their function and their remarkable specificity. CRLs [Cullin-RING (really interesting new gene) ligases] are the largest group of E3 ligases and function as modular multisubunit complexes constructed around a Cullin-family scaffold protein. The Cul3-based CRLs uniquely assemble with BTB (broad complex/tramtrack/bric-à-brac) proteins that also homodimerize and perform the role of both the Cullin adapter and the substrate-recognition component of the E3. The most prominent member is the BTB-BACK (BTB and C-terminal Kelch)-Kelch protein KEAP1 (Kelch-like ECH-associated protein 1), a master regulator of the oxidative stress response and a potential drug target for common conditions such as diabetes, Alzheimer's disease and Parkinson's disease. Structural characterization of BTB-Cul3 complexes has revealed a number of critical assembly mechanisms, including the binding of an N-terminal Cullin extension to a bihelical '3-box' at the C-terminus of the BTB domain. Improved understanding of the structure of these complexes should contribute significantly to the effort to develop novel therapeutics targeted to CRL3-regulated pathways.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=pmid_dedup__::839c55b704708e46a63bc6a374e7ab21Test
https://ora.ox.ac.uk/objects/uuid:92171bca-21d7-40fe-9f4e-b174e8406f7dTest