دورية أكاديمية
Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon.
| العنوان: | Ligand-mediated protein degradation reveals functional conservation among sequence variants of the CUL4-type E3 ligase substrate receptor cereblon. |
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| المؤلفون: | Akuffo AA; From the Department of Immunology.; the Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612., Alontaga AY; From the Department of Immunology., Metcalf R; the Department of Chemistry and., Beatty MS; From the Department of Immunology., Becker A; the Chemical Biology Core, and., McDaniel JM; From the Department of Immunology., Hesterberg RS; From the Department of Immunology.; the Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida 33612., Goodheart WE; From the Department of Immunology., Gunawan S; the Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612., Ayaz M; the Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612., Yang Y; the Chemical Biology Core, and., Karim MR; the Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612., Orobello ME; From the Department of Immunology., Daniel K; the Department of Chemistry and., Guida W; the Department of Chemistry and., Yoder JA; the Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, and., Rajadhyaksha AM; Pediatric Neurology, Pediatrics, Brain and Mind Research Institute, Graduate Program in Neuroscience, Weill Cornell Medicine, Molecular and Developmental Neuroscience Laboratory, New York, New York 10065., Schönbrunn E; the Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612., Lawrence HR; the Chemical Biology Core, and., Lawrence NJ; the Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612., Epling-Burnette PK; From the Department of Immunology, Pearlie.Burnette@moffitt.org. |
| المصدر: | The Journal of biological chemistry [J Biol Chem] 2018 Apr 20; Vol. 293 (16), pp. 6187-6200. Date of Electronic Publication: 2018 Feb 15. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Country of Publication: United States NLM ID: 2985121R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1083-351X (Electronic) Linking ISSN: 00219258 NLM ISO Abbreviation: J Biol Chem Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2021- : [New York, NY] : Elsevier Inc. on behalf of American Society for Biochemistry and Molecular Biology Original Publication: Baltimore, MD : American Society for Biochemistry and Molecular Biology |
| مواضيع طبية MeSH: | Proteolysis*, Cullin Proteins/*metabolism , Peptide Hydrolases/*chemistry , Peptide Hydrolases/*metabolism , Ubiquitin-Protein Ligases/*metabolism, Adaptor Proteins, Signal Transducing ; Animals ; Azepines/pharmacology ; Cell Cycle Proteins ; Cell Line, Tumor ; Conserved Sequence ; Humans ; Immunologic Factors/metabolism ; Immunologic Factors/pharmacology ; Lenalidomide/pharmacology ; Ligands ; Mice ; Molecular Probes ; Nuclear Proteins/drug effects ; Nuclear Proteins/metabolism ; Proteasome Endopeptidase Complex/metabolism ; T-Lymphocytes/metabolism ; Thalidomide/analogs & derivatives ; Thalidomide/metabolism ; Thalidomide/pharmacology ; Transcription Factors/drug effects ; Transcription Factors/metabolism ; Triazoles/pharmacology ; Ubiquitin/metabolism |
| مستخلص: | Upon binding to thalidomide and other immunomodulatory drugs, the E3 ligase substrate receptor cereblon (CRBN) promotes proteosomal destruction by engaging the DDB1-CUL4A-Roc1-RBX1 E3 ubiquitin ligase in human cells but not in mouse cells, suggesting that sequence variations in CRBN may cause its inactivation. Therapeutically, CRBN engagers have the potential for broad applications in cancer and immune therapy by specifically reducing protein expression through targeted ubiquitin-mediated degradation. To examine the effects of defined sequence changes on CRBN's activity, we performed a comprehensive study using complementary theoretical, biophysical, and biological assays aimed at understanding CRBN's nonprimate sequence variations. With a series of recombinant thalidomide-binding domain (TBD) proteins, we show that CRBN sequence variants retain their drug-binding properties to both classical immunomodulatory drugs and dBET1, a chemical compound and targeting ligand designed to degrade bromodomain-containing 4 (BRD4) via a CRBN-dependent mechanism. We further show that dBET1 stimulates CRBN's E3 ubiquitin-conjugating function and degrades BRD4 in both mouse and human cells. This insight paves the way for studies of CRBN-dependent proteasome-targeting molecules in nonprimate models and provides a new understanding of CRBN's substrate-recruiting function. (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.) |
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| معلومات مُعتمدة: | P30 CA076292 United States CA NCI NIH HHS; R50 CA211447 United States CA NCI NIH HHS |
| فهرسة مساهمة: | Keywords: E3 ubiquitin ligase; bromodomain-containing protein 4 (BRD4); immunology; mouse; multiple myeloma; proteasome; ubiquitin |
| سلسلة جزيئية: | PDB 4TZ4; 4CI2; 4CI1; 4CI3; 4TZC; 4TZU; 5FQD |
| المشرفين على المادة: | 0 ((+)-JQ1 compound) 0 (Adaptor Proteins, Signal Transducing) 0 (Azepines) 0 (BRD4 protein, human) 0 (Brd4 protein, mouse) 0 (CRBN protein, human) 0 (CUL4A protein, human) 0 (Cell Cycle Proteins) 0 (Cul4a protein, mouse) 0 (Cullin Proteins) 0 (Immunologic Factors) 0 (Ligands) 0 (Molecular Probes) 0 (Nuclear Proteins) 0 (Transcription Factors) 0 (Triazoles) 0 (Ubiquitin) 0 (dBET1 compound) 4Z8R6ORS6L (Thalidomide) EC 2.3.2.27 (Ubiquitin-Protein Ligases) EC 3.4.- (Peptide Hydrolases) EC 3.4.25.1 (Proteasome Endopeptidase Complex) F0P408N6V4 (Lenalidomide) |
| تواريخ الأحداث: | Date Created: 20180217 Date Completed: 20190109 Latest Revision: 20210205 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5912449 |
| DOI: | 10.1074/jbc.M117.816868 |
| PMID: | 29449372 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1083-351X |
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| DOI: | 10.1074/jbc.M117.816868 |