Structural highlights
Function
CNOT6_HUMAN Poly(A) nuclease with 3'-5' RNase activity. Catalytic component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational initiation and general transcription regulation. Additional complex functions may be a consequence of its influence on mRNA expression. Involved in mRNA decay mediated by the major-protein-coding determinant of instability (mCRD) of the FOS gene in the cytoplasm. In the presence of ZNF335, enhances ligand-dependent transcriptional activity of nuclear hormone receptors, including RARA. The increase of ligand-dependent ESR1-mediated transcription is much smaller, if any. Mediates cell proliferation and cell survival and prevents cellular senescence.[1] [2] [3] [4]
Publication Abstract from PubMed
The CCR4 and CAF1 deadenylases physically interact to form the CCR4-CAF1 complex and function as the catalytic core of the larger CCR4-NOT complex. Together, they are responsible for the eventual removal of the 3'-poly(A) tail from essentially all cellular mRNAs and consequently play a central role in the posttranscriptional regulation of gene expression. The individual properties of CCR4 and CAF1, however, and their respective contributions in different organisms and cellular environments are incompletely understood. Here, we determined the crystal structure of a human CCR4-CAF1 complex and characterized its enzymatic and substrate recognition properties. The structure reveals specific molecular details affecting RNA binding and hydrolysis, and confirms the CCR4 nuclease domain to be tethered flexibly with a considerable distance between both enzyme active sites. CCR4 and CAF1 sense nucleotide identity on both sides of the 3'-terminal phosphate, efficiently differentiating between single and consecutive non-A residues. In comparison to CCR4, CAF1 emerges as a surprisingly tunable enzyme, highly sensitive to pH, magnesium and zinc ions, and possibly allowing distinct reaction geometries. Our results support a picture of CAF1 as a primordial deadenylase, which gets assisted by CCR4 for better efficiency and by the assembled NOT proteins for selective mRNA targeting and regulation.
Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex.,Chen Y, Khazina E, Izaurralde E, Weichenrieder O Nucleic Acids Res. 2021 Jun 21;49(11):6489-6510. doi: 10.1093/nar/gkab414. PMID:34038562[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chen J, Chiang YC, Denis CL. CCR4, a 3'-5' poly(A) RNA and ssDNA exonuclease, is the catalytic component of the cytoplasmic deadenylase. EMBO J. 2002 Mar 15;21(6):1414-26. PMID:11889047 doi:http://dx.doi.org/10.1093/emboj/21.6.1414
- ↑ Garapaty S, Mahajan MA, Samuels HH. Components of the CCR4-NOT complex function as nuclear hormone receptor coactivators via association with the NRC-interacting Factor NIF-1. J Biol Chem. 2008 Mar 14;283(11):6806-16. doi: 10.1074/jbc.M706986200. Epub 2008 , Jan 7. PMID:18180299 doi:http://dx.doi.org/10.1074/jbc.M706986200
- ↑ Piao X, Zhang X, Wu L, Belasco JG. CCR4-NOT deadenylates mRNA associated with RNA-induced silencing complexes in human cells. Mol Cell Biol. 2010 Mar;30(6):1486-94. PMID:20065043 doi:10.1128/MCB.01481-09
- ↑ Mittal S, Aslam A, Doidge R, Medica R, Winkler GS. The Ccr4a (CNOT6) and Ccr4b (CNOT6L) deadenylase subunits of the human Ccr4-Not complex contribute to the prevention of cell death and senescence. Mol Biol Cell. 2011 Mar 15;22(6):748-58. PMID:21233283 doi:10.1091/mbc.E10-11-0898
- ↑ Chen Y, Khazina E, Izaurralde E, Weichenrieder O. Crystal structure and functional properties of the human CCR4-CAF1 deadenylase complex. Nucleic Acids Res. 2021 Jun 21;49(11):6489-6510. PMID:34038562 doi:10.1093/nar/gkab414
