6zot | pdb_00006zot

Crystal structure of YTHDF3 YTH domain in complex with m6A RNA

Structural highlights

6zot is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.7Å
Ligands:	6MZ
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

YTHD3_HUMAN Specifically recognizes and binds N6-methyladenosine (m6A)-containing RNAs, and regulates their stability (PubMed:28106072, PubMed:28106076, PubMed:28281539, PubMed:32492408). M6A is a modification present at internal sites of mRNAs and some non-coding RNAs and plays a role in mRNA stability and processing (PubMed:22575960, PubMed:24284625, PubMed:28106072, PubMed:28281539, PubMed:32492408). Acts as a regulator of mRNA stability by promoting degradation of m6A-containing mRNAs via interaction with the CCR4-NOT complex or PAN3 (PubMed:32492408). The YTHDF paralogs (YTHDF1, YTHDF2 and YTHDF3) share m6A-containing mRNAs targets and act redundantly to mediate mRNA degradation and cellular differentiation (PubMed:28106072, PubMed:28106076, PubMed:32492408). Acts as a negative regulator of type I interferon response by down-regulating interferon-stimulated genes (ISGs) expression: acts by binding to FOXO3 mRNAs (By similarity). Binds to FOXO3 mRNAs independently of METTL3-mediated m6A modification (By similarity). Can also act as a regulator of mRNA stability in cooperation with YTHDF2 by binding to m6A-containing mRNA and promoting their degradation (PubMed:28106072). Recognizes and binds m6A-containing circular RNAs (circRNAs); circRNAs are generated through back-splicing of pre-mRNAs, a non-canonical splicing process promoted by dsRNA structures across circularizing exons (PubMed:28281539). Promotes formation of phase-separated membraneless compartments, such as P-bodies or stress granules, by undergoing liquid-liquid phase separation upon binding to mRNAs containing multiple m6A-modified residues: polymethylated mRNAs act as a multivalent scaffold for the binding of YTHDF proteins, juxtaposing their disordered regions and thereby leading to phase separation (PubMed:31388144, PubMed:31292544, PubMed:32451507). The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated membraneless compartments, such as P-bodies, stress granules or neuronal RNA granules (PubMed:31292544). May also recognize and bind N1-methyladenosine (m1A)-containing mRNAs: inhibits trophoblast invasion by binding to m1A-methylated transcripts of IGF1R, promoting their degradation (PubMed:32194978).[UniProtKB:Q8BYK6]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] Has some antiviral activity against HIV-1 virus: incorporated into HIV-1 particles in a nucleocapsid-dependent manner and reduces viral infectivity in the next cycle of infection (PubMed:32053707). May interfere with this early step of the viral life cycle by binding to N6-methyladenosine (m6A) modified sites on the HIV-1 RNA genome (PubMed:32053707).^[11]

Publication Abstract from PubMed

Three YTH-domain family proteins (YTHDF1, YTHDF2, and YTHDF3) recognize the N(6)-methyladenosine (m(6)A) modification of mRNA in cells. However, the redundancy of their cellular functions has been disputed. We investigate their interactions with m(6)A-containing RNA using X-ray crystallography and molecular dynamics (MD). The new X-ray structures and MD simulations show that the three proteins share identical interactions with the m(6)A-containing RNA and have similar intrinsic plasticity, thus evidencing the redundant roles of the three proteins in cellular functions.

Structural and Dynamic Insights into Redundant Function of YTHDF Proteins.,Li Y, Bedi RK, Moroz-Omori EV, Caflisch A J Chem Inf Model. 2020 Dec 28;60(12):5932-5935. doi: 10.1021/acs.jcim.0c01029. , Epub 2020 Oct 19. PMID:33073985^[12]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112. PMID:22575960 doi:https://dx.doi.org/10.1038/nature11112
↑ Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27. PMID:24284625 doi:https://dx.doi.org/10.1038/nature12730
↑ Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017 Mar;27(3):315-328. PMID:28106072 doi:10.1038/cr.2017.15
↑ Li A, Chen YS, Ping XL, Yang X, Xiao W, Yang Y, Sun HY, Zhu Q, Baidya P, Wang X, Bhattarai DP, Zhao YL, Sun BF, Yang YG. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 2017 Mar;27(3):444-447. PMID:28106076 doi:10.1038/cr.2017.10
↑ Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, Jin Y, Yang Y, Chen LL, Wang Y, Wong CC, Xiao X, Wang Z. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017 May;27(5):626-641. PMID:28281539 doi:10.1038/cr.2017.31
↑ Ries RJ, Zaccara S, Klein P, Olarerin-George A, Namkoong S, Pickering BF, Patil DP, Kwak H, Lee JH, Jaffrey SR. m(6)A enhances the phase separation potential of mRNA. Nature. 2019 Jul;571(7765):424-428. PMID:31292544 doi:10.1038/s41586-019-1374-1
↑ Gao Y, Pei G, Li D, Li R, Shao Y, Zhang QC, Li P. Multivalent m(6)A motifs promote phase separation of YTHDF proteins. Cell Res. 2019 Sep;29(9):767-769. PMID:31388144 doi:10.1038/s41422-019-0210-3
↑ Zheng Q, Gan H, Yang F, Yao Y, Hao F, Hong L, Jin L. Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov. 2020 Mar 10;6:12. PMID:32194978 doi:10.1038/s41421-020-0144-4
↑ Fu Y, Zhuang X. m(6)A-binding YTHDF proteins promote stress granule formation. Nat Chem Biol. 2020 Sep;16(9):955-963. PMID:32451507 doi:10.1038/s41589-020-0524-y
↑ Zaccara S, Jaffrey SR. A Unified Model for the Function of YTHDF Proteins in Regulating m(6)A-Modified mRNA. Cell. 2020 Jun 25;181(7):1582-1595.e18. PMID:32492408 doi:10.1016/j.cell.2020.05.012
↑ Jurczyszak D, Zhang W, Terry SN, Kehrer T, Bermúdez González MC, McGregor E, Mulder LCF, Eckwahl MJ, Pan T, Simon V. HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle. PLoS Pathog. 2020 Feb 13;16(2):e1008305. PMID:32053707 doi:10.1371/journal.ppat.1008305
↑ Li Y, Bedi RK, Moroz-Omori EV, Caflisch A. Structural and Dynamic Insights into Redundant Function of YTHDF Proteins. J Chem Inf Model. 2020 Dec 28;60(12):5932-5935. PMID:33073985 doi:10.1021/acs.jcim.0c01029

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OCA

[1] Dominissini D, Moshitch-Moshkovitz S, Schwartz S, Salmon-Divon M, Ungar L, Osenberg S, Cesarkas K, Jacob-Hirsch J, Amariglio N, Kupiec M, Sorek R, Rechavi G. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012 Apr 29;485(7397):201-6. doi: 10.1038/nature11112. PMID:22575960 doi:https://dx.doi.org/10.1038/nature11112

[2] Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, Fu Y, Parisien M, Dai Q, Jia G, Ren B, Pan T, He C. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014 Jan 2;505(7481):117-20. doi: 10.1038/nature12730. Epub 2013 Nov 27. PMID:24284625 doi:https://dx.doi.org/10.1038/nature12730

[3] Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, Liu C, He C. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017 Mar;27(3):315-328. PMID:28106072 doi:10.1038/cr.2017.15

[4] Li A, Chen YS, Ping XL, Yang X, Xiao W, Yang Y, Sun HY, Zhu Q, Baidya P, Wang X, Bhattarai DP, Zhao YL, Sun BF, Yang YG. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 2017 Mar;27(3):444-447. PMID:28106076 doi:10.1038/cr.2017.10

[5] Yang Y, Fan X, Mao M, Song X, Wu P, Zhang Y, Jin Y, Yang Y, Chen LL, Wang Y, Wong CC, Xiao X, Wang Z. Extensive translation of circular RNAs driven by N(6)-methyladenosine. Cell Res. 2017 May;27(5):626-641. PMID:28281539 doi:10.1038/cr.2017.31

[6] Ries RJ, Zaccara S, Klein P, Olarerin-George A, Namkoong S, Pickering BF, Patil DP, Kwak H, Lee JH, Jaffrey SR. m(6)A enhances the phase separation potential of mRNA. Nature. 2019 Jul;571(7765):424-428. PMID:31292544 doi:10.1038/s41586-019-1374-1

[7] Gao Y, Pei G, Li D, Li R, Shao Y, Zhang QC, Li P. Multivalent m(6)A motifs promote phase separation of YTHDF proteins. Cell Res. 2019 Sep;29(9):767-769. PMID:31388144 doi:10.1038/s41422-019-0210-3

[8] Zheng Q, Gan H, Yang F, Yao Y, Hao F, Hong L, Jin L. Cytoplasmic m(1)A reader YTHDF3 inhibits trophoblast invasion by downregulation of m(1)A-methylated IGF1R. Cell Discov. 2020 Mar 10;6:12. PMID:32194978 doi:10.1038/s41421-020-0144-4

[9] Fu Y, Zhuang X. m(6)A-binding YTHDF proteins promote stress granule formation. Nat Chem Biol. 2020 Sep;16(9):955-963. PMID:32451507 doi:10.1038/s41589-020-0524-y

[10] Zaccara S, Jaffrey SR. A Unified Model for the Function of YTHDF Proteins in Regulating m(6)A-Modified mRNA. Cell. 2020 Jun 25;181(7):1582-1595.e18. PMID:32492408 doi:10.1016/j.cell.2020.05.012

[11] Jurczyszak D, Zhang W, Terry SN, Kehrer T, Bermúdez González MC, McGregor E, Mulder LCF, Eckwahl MJ, Pan T, Simon V. HIV protease cleaves the antiviral m6A reader protein YTHDF3 in the viral particle. PLoS Pathog. 2020 Feb 13;16(2):e1008305. PMID:32053707 doi:10.1371/journal.ppat.1008305

[12] Li Y, Bedi RK, Moroz-Omori EV, Caflisch A. Structural and Dynamic Insights into Redundant Function of YTHDF Proteins. J Chem Inf Model. 2020 Dec 28;60(12):5932-5935. PMID:33073985 doi:10.1021/acs.jcim.0c01029

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6zot | pdb_00006zot

Crystal structure of YTHDF3 YTH domain in complex with m6A RNA

Structural highlights

Function

Publication Abstract from PubMed

References

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