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Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM.

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Ripin N, Boudet J, Duszczyk MM, Hinniger A, Faller M, Krepl M, Gadi A, Schneider RJ, Šponer J, Meisner-Kober NC, Allain FH
OpenAccess logo Proc Natl Acad Sci U S A 116 2935-2944 (2019)
Cited: 47 times
EuropePMC logo PMID: 30718402

Abstract

Human antigen R (HuR) is a key regulator of cellular mRNAs containing adenylate/uridylate-rich elements (AU-rich elements; AREs). These are a major class of cis elements within 3' untranslated regions, targeting these mRNAs for rapid degradation. HuR contains three RNA recognition motifs (RRMs): a tandem RRM1 and 2, followed by a flexible linker and a C-terminal RRM3. While RRM1 and 2 are structurally characterized, little is known about RRM3. Here we present a 1.9-Å-resolution crystal structure of RRM3 bound to different ARE motifs. This structure together with biophysical methods and cell-culture assays revealed the mechanism of RRM3 ARE recognition and dimerization. While multiple RNA motifs can be bound, recognition of the canonical AUUUA pentameric motif is possible by binding to two registers. Additionally, RRM3 forms homodimers to increase its RNA binding affinity. Finally, although HuR stabilizes ARE-containing RNAs, we found that RRM3 counteracts this effect, as shown in a cell-based ARE reporter assay and by qPCR with native HuR mRNA targets containing multiple AUUUA motifs, possibly by competing with RRM12.

Articles - 6gc5 mentioned but not cited (6)

  1. A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus. Simion V, Zhou H, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, Pérez-Cremades D, Lee JF, Chen AF, Ronda N, Papotti B, Marto JA, Feinberg MW. Nat Commun 11 6135 (2020)
  2. Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM. Ripin N, Boudet J, Duszczyk MM, Hinniger A, Faller M, Krepl M, Gadi A, Schneider RJ, Šponer J, Meisner-Kober NC, Allain FH. Proc Natl Acad Sci U S A 116 2935-2944 (2019)
  3. Circular RNA circStag1 promotes bone regeneration by interacting with HuR. Chen G, Long C, Wang S, Wang Z, Chen X, Tang W, He X, Bao Z, Tan B, Zhao J, Xie Y, Li Z, Yang D, Xiao G, Peng S. Bone Res 10 32 (2022)
  4. Molecular basis for PICS-mediated piRNA biogenesis and cell division. Wang X, Zeng C, Liao S, Zhu Z, Zhang J, Tu X, Yao X, Feng X, Guang S, Xu C. Nat Commun 12 5595 (2021)
  5. Spontaneous binding of single-stranded RNAs to RRM proteins visualized by unbiased atomistic simulations with a rescaled RNA force field. Krepl M, Pokorná P, Mlýnský V, Stadlbauer P, Šponer J. Nucleic Acids Res 50 12480-12496 (2022)
  6. Exosomal circSPIRE1 mediates glycosylation of E-cadherin to suppress metastasis of renal cell carcinoma. Shu G, Lu X, Pan Y, Cen J, Huang K, Zhou M, Lu J, Dong J, Han H, Chen W, Lin J, Luo J, Zhang J. Oncogene 42 1802-1820 (2023)


Reviews citing this publication (17)

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  7. The versatile role of HuR in Glioblastoma and its potential as a therapeutic target for a multi-pronged attack. Guha A, Waris S, Nabors LB, Filippova N, Gorospe M, Kwan T, King PH. Adv Drug Deliv Rev 181 114082 (2022)
  8. Roles of Embryonic Lethal Abnormal Vision-Like RNA Binding Proteins in Cancer and Beyond. Cai H, Zheng D, Yao Y, Yang L, Huang X, Wang L. Front Cell Dev Biol 10 847761 (2022)
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  11. Alternative Polyadenylation Is a Novel Strategy for the Regulation of Gene Expression in Response to Stresses in Plants. Wu J, Ma L, Cao Y. Int J Mol Sci 24 4727 (2023)
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  13. RNA-Binding Proteins in the Regulation of Adipogenesis and Adipose Function. Zhang P, Wu W, Ma C, Du C, Huang Y, Xu H, Li C, Cheng X, Hao R, Xu Y. Cells 11 2357 (2022)
  14. The androgen receptor messenger RNA: what do we know? Likos E, Bhattarai A, Weyman CM, Shukla GC. RNA Biol 19 819-828 (2022)
  15. The molecular genetics of nELAVL in brain development and disease. Mulligan MR, Bicknell LS. Eur J Hum Genet 31 1209-1217 (2023)
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