HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
25 01 2019
25 01 2019
Historique:
received:
01
08
2018
accepted:
28
10
2018
pubmed:
13
11
2018
medline:
21
8
2019
entrez:
13
11
2018
Statut:
ppublish
Résumé
HuR/ELAVL1 is an RNA-binding protein involved in differentiation and stress response that acts primarily by stabilizing messenger RNA (mRNA) targets. HuR comprises three RNA recognition motifs (RRMs) where the structure and RNA binding of RRM3 and of full-length HuR remain poorly understood. Here, we report crystal structures of RRM3 free and bound to cognate RNAs. Our structural, NMR and biochemical data show that RRM3 mediates canonical RNA interactions and reveal molecular details of a dimerization interface localized on the α-helical face of RRM3. NMR and SAXS analyses indicate that the three RRMs in full-length HuR are flexibly connected in the absence of RNA, while they adopt a more compact arrangement when bound to RNA. Based on these data and crystal structures of tandem RRM1,2-RNA and our RRM3-RNA complexes, we present a structural model of RNA recognition involving all three RRM domains of full-length HuR. Mutational analysis demonstrates that RRM3 dimerization and RNA binding is required for functional activity of full-length HuR in vitro and to regulate target mRNAs levels in human cells, thus providing a fine-tuning for HuR activity in vivo.
Identifiants
pubmed: 30418581
pii: 5168822
doi: 10.1093/nar/gky1138
pmc: PMC6344896
doi:
Substances chimiques
ELAV-Like Protein 1
0
ELAVL1 protein, human
0
RNA
63231-63-0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1011-1029Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM103408
Pays : United States
Références
Nucleic Acids Res. 1997 Sep 15;25(18):3564-9
pubmed: 9278474
J Biol Chem. 2011 Oct 28;286(43):37063-6
pubmed: 21890634
EMBO J. 2000 May 15;19(10):2340-50
pubmed: 10811625
Nat Chem Biol. 2007 Aug;3(8):508-15
pubmed: 17632515
J Biol Chem. 2007 Jul 20;282(29):20948-59
pubmed: 17517897
Cell Signal. 2013 Dec;25(12):2485-95
pubmed: 23978401
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8354-9
pubmed: 12821781
Mol Cell Biol. 2000 Feb;20(3):760-9
pubmed: 10629032
Protein Sci. 2008 Dec;17(12):2070-9
pubmed: 18780816
Wiley Interdiscip Rev RNA. 2010 Sep-Oct;1(2):214-29
pubmed: 21935886
EMBO J. 1998 Jun 15;17(12):3448-60
pubmed: 9628880
Acta Crystallogr D Biol Crystallogr. 2004 Dec;60(Pt 12 Pt 1):2256-68
pubmed: 15572779
Mol Cell. 2011 Aug 5;43(3):327-39
pubmed: 21723170
Curr Protein Pept Sci. 2012 Jun;13(4):372-9
pubmed: 22708488
Mol Cell. 2011 Aug 5;43(3):340-52
pubmed: 21723171
Nucleic Acids Res. 2014 May;42(9):5949-66
pubmed: 24682828
Genes Dev. 2013 May 1;27(9):1046-58
pubmed: 23618873
Nucleic Acids Res. 2011 Feb;39(3):1117-30
pubmed: 21233170
Nucleic Acids Res. 2006;34(17):4943-59
pubmed: 16982642
J Mol Biol. 2010 Jul 9;400(2):145-54
pubmed: 20460131
Hepatology. 2012 Apr;55(4):1237-48
pubmed: 22095636
BMC Genomics. 2008 Aug 20;9:392
pubmed: 18715504
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2987-92
pubmed: 14981256
Mol Cell Biol. 2014 Aug;34(15):2857-73
pubmed: 24865968
Mol Cell. 2007 Feb 23;25(4):543-57
pubmed: 17317627
Genes Dev. 2002 Dec 1;16(23):3087-99
pubmed: 12464637
Crit Rev Oncol Hematol. 1994 Oct;17(2):93-131
pubmed: 7818789
Curr Opin Genet Dev. 2013 Feb;23(1):35-43
pubmed: 23312841
J Cell Biol. 2008 Jan 14;180(1):113-27
pubmed: 18180367
Mol Cell Biol. 2002 Oct;22(20):7268-78
pubmed: 12242302
Prog Nucl Magn Reson Spectrosc. 2014 Jul;80:26-63
pubmed: 24924266
J Biomol NMR. 1995 Nov;6(3):277-93
pubmed: 8520220
Cell Mol Life Sci. 2012 Feb;69(4):501-17
pubmed: 21909784
J Biomol NMR. 2012 Jul;53(3):209-21
pubmed: 22689066
J Biol Chem. 1996 Apr 5;271(14):8144-51
pubmed: 8626503
Curr Opin Struct Biol. 2012 Jun;22(3):287-96
pubmed: 22516180
Mol Cell Neurosci. 2013 Sep;56:447-55
pubmed: 23439364
Nat Struct Biol. 2001 Feb;8(2):141-5
pubmed: 11175903
FEBS Lett. 2015 Apr 28;589(10):1059-66
pubmed: 25841336
Cell Signal. 2008 Dec;20(12):2165-73
pubmed: 18585896
Curr Opin Struct Biol. 2008 Jun;18(3):290-8
pubmed: 18515081
Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):E7169-E7175
pubmed: 27799531
Nucleic Acids Res. 2010 Apr;38(7):2256-67
pubmed: 20064878
Front Mol Biosci. 2016 Sep 13;3:54
pubmed: 27679800
RNA Biol. 2014;11(10):1250-61
pubmed: 25584704
Nucleic Acids Res. 2010 Aug;38(15):5193-205
pubmed: 20385598
Oncogene. 2003 Oct 16;22(46):7146-54
pubmed: 14562043
EMBO J. 2005 May 18;24(10):1852-62
pubmed: 15861128
Acta Crystallogr D Biol Crystallogr. 2013 Mar;69(Pt 3):373-80
pubmed: 23519412
Mol Cell Biol. 2005 Sep;25(17):7580-91
pubmed: 16107705
J Cell Biol. 2000 Oct 2;151(1):1-14
pubmed: 11018049
Nat Biotechnol. 2009 Jul;27(7):667-70
pubmed: 19561594
Biochem Soc Trans. 2010 Aug;38(4):1122-4
pubmed: 20659015
J Am Chem Soc. 2014 May 14;136(19):7068-76
pubmed: 24734879
FEBS J. 2005 May;272(9):2118-31
pubmed: 15853797
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2918-23
pubmed: 14981248
Protein Pept Lett. 2015;22(9):801-15
pubmed: 26149400
Cell Mol Life Sci. 2008 Oct;65(20):3168-81
pubmed: 18581050
Nucleic Acids Res. 2012 Jun;40(11):5088-100
pubmed: 22362743
Nucleic Acids Res. 2009 Aug;37(15):5151-66
pubmed: 19553194
Pancreatology. 2015 Jul;15(4 Suppl):S49-54
pubmed: 25841271
J Biol Chem. 2005 Jul 1;280(26):24768-74
pubmed: 15863502
Nature. 2011 Jul 13;475(7356):408-11
pubmed: 21753750
Mol Cell Biol. 2009 May;29(10):2762-76
pubmed: 19307312
Nucleic Acids Res. 2012 Jan;40(2):787-800
pubmed: 21948791
Mol Cell Biol. 2008 Jan;28(1):93-107
pubmed: 17967866
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15293-8
pubmed: 9860962
J Appl Crystallogr. 2012 Mar 15;45(Pt 2):342-350
pubmed: 25484842
Nucleic Acids Res. 2008 Mar;36(4):1390-9
pubmed: 18203745
Mol Cell Biol. 2010 Mar;30(6):1397-410
pubmed: 20086103