| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Wei, Ning Ding, Yan Xu, Jing Scherer, Paul C. Zheng, Ning Snyder, Solomon H. Rao, Feng Barrow, James C. Liu, Zhiqing Mao, Haibin |
| Description |
Author Affiliation: Scherer PC ( The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205); Ding Y ( National Institute of Biological Sciences, Beijing 102206, China); Liu Z ( National Institute of Biological Sciences, Beijing 102206, China); Xu J ( The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205); Mao H ( Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195); Barrow JC ( Department of Pharmacology and Molecular Science, Lieber Institute for Brain Development, The Johns Hopkins University School of Medicine, Baltimore, MD 21205); Wei N ( Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511); Zheng N ( Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195); Snyder SH ( The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21205); Rao F ( National Institute of Biological Sciences, Beijing 102206, China); |
| Abstract |
The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL–CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an $EC_{50}$ of 20 nM, acts as an intermolecular “glue,” increasing cullin–CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL–CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL–CSN system and are potential targets for cancer therapy in conjunction with MLN4924. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
13 |
| Volume Number |
113 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2016-04-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Cullin Proteins Metabolism Multiprotein Complexes Peptide Hydrolases Phosphotransferases (Phosphate Group Acceptor) Phytic Acid Biosynthesis Amino Acid Sequence Catalytic Domain Chemistry Genetics Enzyme Stability Gene Knockdown Techniques HEK293 Cells Models, Molecular Molecular Sequence Data Antagonists & Inhibitors Protein Interaction Domains And Motifs Sequence Homology, Amino Acid Static Electricity Ubiquitin-Protein Ligases Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
