5k7u

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(Difference between revisions)

Revision as of 07:37, 24 April 2019

Crystal structure of the catalytic domains of Mettl3/Mettl14 complex with SAM

Structural highlights

5k7u is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	5k7w, 5k7m
Gene:	METTL3, MTA70 (HUMAN), METTL14, KIAA1627 (HUMAN)
Activity:	mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase, with EC number 2.1.1.62
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[MTA70_HUMAN] N6-methyltransferase that methylates adenosine residues of some RNAs and acts as a regulator of the circadian clock, differentiation of embryonic stem cells and primary miRNA processing. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing, translation efficiency, editing and mRNA stability (PubMed:22575960, PubMed:24284625, PubMed:25719671, PubMed:25799998, PubMed:26321680, PubMed:26593424, PubMed:9409616). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop by putting mRNA production on a fast-track for facilitating nuclear processing, thereby providing an early point of control in setting the dynamics of the feedback loop (By similarity). M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization, promoting differentiation of ESCs (By similarity). M6A also takes place in other RNA molecules, such as primary miRNA (pri-miRNAs) (PubMed:25799998). Mediates methylation of pri-miRNAs, marking them for recognition and processing by DGCR8 (PubMed:25799998).[UniProtKB:Q8C3P7]^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] [MET14_HUMAN] N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4]^[8] ^[9] ^[10]

Publication Abstract from PubMed

N(6)-methyladenosine (m(6)A) is a prevalent, reversible chemical modification of functional RNAs and is important for central events in biology. The core m(6)A writers are Mettl3 and Mettl14, which both contain methyltransferase domains. How Mettl3 and Mettl14 cooperate to catalyze methylation of adenosines has remained elusive. We present crystal structures of the complex of Mettl3/Mettl14 methyltransferase domains in apo form as well as with bound S-adenosylmethionine (SAM) or S-adenosylhomocysteine (SAH) in the catalytic site. We determine that the heterodimeric complex of methyltransferase domains, combined with CCCH motifs, constitutes the minimally required regions for creating m(6)A modifications in vitro. We also show that Mettl3 is the catalytically active subunit, while Mettl14 plays a structural role critical for substrate recognition. Our model provides a molecular explanation for why certain mutations of Mettl3 and Mettl14 lead to impaired function of the methyltransferase complex.

Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases.,Wang P, Doxtader KA, Nam Y Mol Cell. 2016 Jul 21;63(2):306-17. doi: 10.1016/j.molcel.2016.05.041. Epub 2016 , Jun 30. PMID:27373337^[11]

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:http://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:http://dx.doi.org/10.1038/nature12730
↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
↑ Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015 Mar 26;519(7544):482-5. doi: 10.1038/nature14281. Epub 2015 Mar 18. PMID:25799998 doi:http://dx.doi.org/10.1038/nature14281
↑ Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015 Sep 10;162(6):1299-308. doi: 10.1016/j.cell.2015.08.011. Epub 2015 Aug, 27. PMID:26321680 doi:http://dx.doi.org/10.1016/j.cell.2015.08.011
↑ Meyer KD, Patil DP, Zhou J, Zinoviev A, Skabkin MA, Elemento O, Pestova TV, Qian SB, Jaffrey SR. 5' UTR m(6)A Promotes Cap-Independent Translation. Cell. 2015 Nov 5;163(4):999-1010. doi: 10.1016/j.cell.2015.10.012. Epub 2015 Oct , 22. PMID:26593424 doi:http://dx.doi.org/10.1016/j.cell.2015.10.012
↑ Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997 Nov;3(11):1233-47. PMID:9409616
↑ Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014 Feb;10(2):93-5. doi: 10.1038/nchembio.1432. Epub 2013 Dec 6. PMID:24316715 doi:http://dx.doi.org/10.1038/nchembio.1432
↑ Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014 Feb;24(2):177-89. doi: 10.1038/cr.2014.3. Epub 2014 Jan 10. PMID:24407421 doi:http://dx.doi.org/10.1038/cr.2014.3
↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
↑ Wang P, Doxtader KA, Nam Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol Cell. 2016 Jul 21;63(2):306-17. doi: 10.1016/j.molcel.2016.05.041. Epub 2016 , Jun 30. PMID:27373337 doi:http://dx.doi.org/10.1016/j.molcel.2016.05.041

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5k7u"

@@ Line 1: / Line 1: @@
 ==Crystal structure of the catalytic domains of Mettl3/Mettl14 complex with SAM==
-<StructureSection load='5k7u' size='340' side='right' caption='[[5k7u]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
+<StructureSection load='5k7u' size='340' side='right'caption='[[5k7u]], [[Resolution|resolution]] 1.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5k7u]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K7U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K7U FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5k7u]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5K7U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5K7U FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SAM:S-ADENOSYLMETHIONINE'>SAM</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5k7w|5k7w]], [[5k7m|5k7m]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">METTL3, MTA70 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), METTL14, KIAA1627 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/mRNA_(2'-O-methyladenosine-N(6)-)-methyltransferase mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.62 2.1.1.62] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5k7u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5k7u OCA], [http://pdbe.org/5k7u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5k7u RCSB], [http://www.ebi.ac.uk/pdbsum/5k7u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5k7u ProSAT]</span></td></tr>
@@ Line 24: / Line 25: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Doxtader, K A]]
 [[Category: Nam, Y]]

5k7u

From Proteopedia

Revision as of 07:37, 24 April 2019

Crystal structure of the catalytic domains of Mettl3/Mettl14 complex with SAM

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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