ELAV-like protein 1

Last updated

ELAVL1
ELAV-like protein 1 (HuR).png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ELAVL1 , ELAV1, HUR, Hua, MelG, ELAV like RNA binding protein 1, HuR
External IDs OMIM: 603466; MGI: 1100851; HomoloGene: 20367; GeneCards: ELAVL1; OMA:ELAVL1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1994

15568

Ensembl

ENSG00000066044

ENSMUSG00000040028

UniProt

Q15717

P70372

RefSeq (mRNA)

NM_001419

NM_010485

RefSeq (protein)

NP_001410

NP_034615

Location (UCSC) Chr 19: 7.96 – 8.01 Mb Chr 8: 4.34 – 4.38 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ELAV-like protein 1 or HuR (human antigen R) is a protein that in humans is encoded by the ELAVL1 gene. [5] [6]

Contents

The protein encoded by this gene is a member of the ELAVL protein family. This encoded protein contains 3 RNA-binding domains and binds cis-acting AU-rich elements in 3' untranslated regions. One of its best-known functions is to stabilize mRNAs in order to regulate gene expression. [7] Various post-translational modifications of HuR influence its subcellular localization and stability of binding to mRNAs. [8]

Structure

Of the RNA-binding ELAV/Hu family of proteins in mammals, HuR is the only ubiquitously expressed one, whereas the other three are primarily found in neuronal tissue. [9] Having a well-conserved primary structure to its family members, HuR has two adjacent RNA recognition motifs (RRMs) proximal to the N-terminus, followed by a flexible hinge region next to a final RRM at the C-terminus. [5] The RRM domains of HuR each contain two alpha helices with several antiparallel beta sheets in their secondary structure, a 20 amino-acid long N-terminus before RRM1 and RRM2, and a 12 amino acid linker connecting them. [10] [11] The hinge region connecting RRM1,2 to RRM3 is 60 amino acids long. [11]

RNA Binding

The RRM1 domain appears to be the principal RNA-binding portion with RRM2 contributing some more contacts. [11] According to crystal structure studies, RRM1,2 domains correspond to a "moderately specific" predicted consensus sequence. [12] [13] Additionally, RRM3 contributes to dimerization and oligomerization of HuR, supporting binding to AU-rich elements of RNA by the other domains, but RRM3 itself has moderate binding strength to RNA. [12] RRM3 has been shown to bind to long poly-A tails and AU-rich RNAs. [14]

Function

This RNA-binding protein has been found to be involved in a number of valuable cellular processes in mammals, including embryonic development, stress responses, and the immune system. [15] Post-translational modifications of HuR, including phosphorylation, NEDDylation, methylation, and ubiquitination each modulate the localization and expression of the protein in unique ways. Modifications such as methylation and ubiquitination alter the affinity of HuR to RNA. [16] As an important regulator of post-transcriptional regulation, HuR destabilization from the mRNA is associated with degradation of the transcript. [17]

Phosphorylation of HuR can occur by cyclin-dependent kinases (cdks), impacting its localization within the cell in a cell cycle-dependent fashion. [18] Additionally, checkpoint kinase 2 plays a significant role in phosphorylating HuR during genotoxic stress, promoting dissociation of HuR from its target mRNA transcript. [19]

Additionally, the ubiquitination of HuR by an E3 ligase in many cases results in proteasomal degradation. For instance, the esophageal tumor suppressor ECRG2, ubiquitinates HuR during DNA damage, promoting its degradation. [20] However, in other cases, ubiquitination promotes dissociation of HuR from its transcript, such as ubiquitination of certain lysine residues of the RRM3 domain leading to detachment from the mRNA transcript of P21 and other tumor suppressors. [21]

Moreover, as is frequent in other mammalian proteins, HuR is methylated at arginine residues. [22] For instance, protein arginine methyltransferase enzymes (PRMTs) methylate HuR to promote mRNA stabilization of certain target transcripts, such as SIRT1 in HeLa cells. [23]

Cancer

Although HuR has a vital role in transcriptosomal regulation, there is an apparent up-regulation of HuR in several types of cancer that correlates with a malignant or metastatic status that has increased the relevance of HuR as a potential therapeutic target for a number of cancer studies. The abundance of HuR suggests a tumorigenic promotion of angiogenesis, cellular proliferation, and anti-apoptotic properties in cancer cells, purportedly due to the impact of mRNA stabilization and its ubiquitous presence in human tissue. [24]

Related Research Articles

RNA-binding proteins are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif (RRM), dsRNA binding domain, zinc finger and others. They are cytoplasmic and nuclear proteins. However, since most mature RNA is exported from the nucleus relatively quickly, most RBPs in the nucleus exist as complexes of protein and pre-mRNA called heterogeneous ribonucleoprotein particles (hnRNPs). RBPs have crucial roles in various cellular processes such as: cellular function, transport and localization. They especially play a major role in post-transcriptional control of RNAs, such as: splicing, polyadenylation, mRNA stabilization, mRNA localization and translation. Eukaryotic cells express diverse RBPs with unique RNA-binding activity and protein–protein interaction. According to the Eukaryotic RBP Database (EuRBPDB), there are 2961 genes encoding RBPs in humans. During evolution, the diversity of RBPs greatly increased with the increase in the number of introns. Diversity enabled eukaryotic cells to utilize RNA exons in various arrangements, giving rise to a unique RNP (ribonucleoprotein) for each RNA. Although RBPs have a crucial role in post-transcriptional regulation in gene expression, relatively few RBPs have been studied systematically. It has now become clear that RNA–RBP interactions play important roles in many biological processes among organisms.

Ribonomics is the study of ribonucleic acids (RNAs) associated with RNA-binding proteins (RBPs). The term was introduced by Robert Cedergren and colleagues who used a bioinformatic search tool to discover novel ribozymes and RNA motifs originally found in HIV. Ribonomics, like genomics or proteomics, is the large-scale, high-throughput approach to identifying subsets of RNAs by their association with proteins in cells. Since many messenger RNAs (mRNAs) are linked with multiple processes, this technique offers a facile mechanism to study the relationship of various intracellular systems. Prokaryotes co-regulate genes common to cellular processes via a polycistronic operon. Since eukaryotic transcription produces mRNA encoding proteins in a monocistronic fashion, many gene products must be concomitantly expressed and translated in a timed fashion. RBPs are thought to be the molecules which physically and biochemically organize these messages to different cellular locales where they may be translated, degraded or stored. The study of transcripts associated with RBPs is therefore thought to be important in eukaryotes as a mechanism for coordinated gene regulation. The likely biochemical processes which account for this regulation are the expedited/delayed degradation of RNA. In addition to the influence on RNA half-life, translation rates are also thought to be altered by RNA-protein interactions. The Drosophila ELAV family, the Puf family in yeast, and the human La, Ro, and FMR proteins are known examples of RBPs, showing the diverse species and processes with which post-transcriptional gene regulation is associated.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

<span class="mw-page-title-main">PAK2</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.

<span class="mw-page-title-main">U2AF2</span> Protein-coding gene in the species Homo sapiens

Splicing factor U2AF 65 kDa subunit is a protein that in humans is encoded by the U2AF2 gene.

<span class="mw-page-title-main">PCBP1</span> Protein-coding gene in the species Homo sapiens

Poly(rC)-binding protein 1 is a protein that in humans is encoded by the PCBP1 gene.

<span class="mw-page-title-main">USF1</span> Protein-coding gene in the species Homo sapiens

Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.

<span class="mw-page-title-main">HuD (protein)</span> Protein found in humans

HuD otherwise known as ELAV-like protein 4 is a protein that in humans is encoded by the ELAVL4 gene.

<span class="mw-page-title-main">SLBP</span> Protein-coding gene in humans

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<span class="mw-page-title-main">CUGBP2</span> Protein-coding gene in the species Homo sapiens

CUGBP, Elav-like family member 2, also known as Etr-3 is a protein that in humans is encoded by the CELF2 gene.

<span class="mw-page-title-main">HNRPH3</span> Protein-coding gene in humans

Heterogeneous nuclear ribonucleoprotein H3 is a protein that in humans is encoded by the HNRNPH3 gene.

<span class="mw-page-title-main">CHD8</span> Protein-coding gene in the species Homo sapiens

Chromodomain-helicase-DNA-binding protein 8 is an enzyme that in humans is encoded by the CHD8 gene.

<span class="mw-page-title-main">RBBP6</span> Protein-coding gene in the species Homo sapiens

Retinoblastoma-binding protein 6 is a protein that in humans is encoded by the RBBP6 gene.

<span class="mw-page-title-main">JADE1</span> Protein-coding gene in the species Homo sapiens

JADE1 is a protein that in humans is encoded by the JADE1 gene.

<span class="mw-page-title-main">RBFOX1</span> Protein-coding gene in the species Homo sapiens

Fox-1 homolog A, also known as ataxin 2-binding protein 1 (A2BP1) or hexaribonucleotide-binding protein 1 (HRNBP1) or RNA binding protein, fox-1 homolog (Rbfox1), is a protein that in humans is encoded by the RBFOX1 gene.

<span class="mw-page-title-main">C20orf27</span> Protein-coding gene in the species Homo sapiens

UPF0687 protein C20orf27 is a protein that in humans is encoded by the C20orf27 gene. It is expressed in the majority of the human tissues. One study on this protein revealed its role in regulating cell cycle, apoptosis, and tumorigenesis via promoting the activation of NFĸB pathway.

<span class="mw-page-title-main">CUGBP Elav-like family member 4</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">RNA recognition motif</span>

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<span class="mw-page-title-main">Zinc finger protein 226</span> Protein found in humans

Zinc finger protein 226 is a protein that in humans is encoded by the ZNF226 gene.

Jack D. Keene is a James B. Duke Professor of Molecular Genetics and Microbiology at Duke University.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000066044 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000040028 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H (April 1996). "Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein". The Journal of Biological Chemistry. 271 (14): 8144–8151. doi: 10.1074/jbc.271.14.8144 . PMID   8626503.
  6. ↑ Ma WJ, Furneaux H (January 1997). "Localization of the human HuR gene to chromosome 19p13.2". Human Genetics. 99 (1): 32–33. doi:10.1007/s004390050305. PMID   9003489. S2CID   32509747.
  7. ↑ "Entrez Gene: ELAVL1 ELAV (embryonic lethal, abnormal vision, Drosophila)-like 1 (Hu antigen R)".
  8. ↑ Doller A, Pfeilschifter J, Eberhardt W (December 2008). "Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR". Cellular Signalling. 20 (12): 2165–2173. doi:10.1016/j.cellsig.2008.05.007. PMID   18585896.
  9. ↑ Antic D, Keene JD (August 1997). "Embryonic lethal abnormal visual RNA-binding proteins involved in growth, differentiation, and posttranscriptional gene expression". American Journal of Human Genetics. 61 (2): 273–278. doi:10.1086/514866. PMC   1715898 . PMID   9311730.
  10. ↑ Cléry A, Blatter M, Allain FH (June 2008). "RNA recognition motifs: boring? Not quite". Current Opinion in Structural Biology. 18 (3): 290–298. doi:10.1016/j.sbi.2008.04.002. PMID   18515081.
  11. 1 2 3 Wang H, Zeng F, Liu Q, Liu H, Liu Z, Niu L, et al. (March 2013). "The structure of the ARE-binding domains of Hu antigen R (HuR) undergoes conformational changes during RNA binding". Acta Crystallographica. Section D, Biological Crystallography. 69 (Pt 3): 373–380. doi:10.1107/S0907444912047828. PMID   23519412.
  12. 1 2 Pabis M, Popowicz GM, Stehle R, Fernández-Ramos D, Asami S, Warner L, et al. (January 2019). "HuR biological function involves RRM3-mediated dimerization and RNA binding by all three RRMs". Nucleic Acids Research. 47 (2): 1011–1029. doi:10.1093/nar/gky1138. PMC   6344896 . PMID   30418581.
  13. ↑ Wang X, Tanaka Hall TM (February 2001). "Structural basis for recognition of AU-rich element RNA by the HuD protein". Nature Structural Biology. 8 (2): 141–145. doi:10.1038/84131. PMID   11175903.
  14. ↑ Ma WJ, Chung S, Furneaux H (September 1997). "The Elav-like proteins bind to AU-rich elements and to the poly(A) tail of mRNA". Nucleic Acids Research. 25 (18): 3564–3569. PMC   146929 . PMID   9278474.
  15. ↑ Katsanou V, Milatos S, Yiakouvaki A, Sgantzis N, Kotsoni A, Alexiou M, et al. (May 2009). "The RNA-binding protein Elavl1/HuR is essential for placental branching morphogenesis and embryonic development". Molecular and Cellular Biology. 29 (10): 2762–2776. doi:10.1128/MCB.01393-08. PMC   2682039 . PMID   19307312.
  16. ↑ Doller A, Pfeilschifter J, Eberhardt W (December 2008). "Signalling pathways regulating nucleo-cytoplasmic shuttling of the mRNA-binding protein HuR". Cellular Signalling. 20 (12): 2165–2173. doi:10.1016/j.cellsig.2008.05.007. PMID   18585896.
  17. ↑ Brennan CM, Steitz JA (February 2001). "HuR and mRNA stability". Cellular and Molecular Life Sciences. 58 (2): 266–277. doi:10.1007/PL00000854. PMC   11146503 . PMID   11289308.
  18. ↑ Kim HH, Abdelmohsen K, Lal A, Pullmann R, Yang X, Galban S, et al. (July 2008). "Nuclear HuR accumulation through phosphorylation by Cdk1". Genes & Development. 22 (13): 1804–1815. doi:10.1101/gad.1645808. PMC   2492667 . PMID   18593881.
  19. ↑ Yu TX, Wang PY, Rao JN, Zou T, Liu L, Xiao L, et al. (October 2011). "Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function". Nucleic Acids Research. 39 (19): 8472–8487. doi:10.1093/nar/gkr567. PMC   3201881 . PMID   21745814.
  20. ↑ Lucchesi C, Sheikh MS, Huang Y (May 2016). "Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2". Oncogene. 35 (20): 2565–2573. doi:10.1038/onc.2015.339. PMID   26434587.
  21. ↑ Zhou HL, Geng C, Luo G, Lou H (May 2013). "The p97-UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP". Genes & Development. 27 (9): 1046–1058. doi:10.1101/gad.215681.113. PMC   3656322 . PMID   23618873.
  22. ↑ Bedford MT, Clarke SG (January 2009). "Protein arginine methylation in mammals: who, what, and why". Molecular Cell. 33 (1): 1–13. doi:10.1016/j.molcel.2008.12.013. PMC   3372459 . PMID   19150423.
  23. ↑ Calvanese V, Lara E, Suárez-Alvarez B, Abu Dawud R, Vázquez-Chantada M, Martínez-Chantar ML, et al. (August 2010). "Sirtuin 1 regulation of developmental genes during differentiation of stem cells". Proceedings of the National Academy of Sciences of the United States of America. 107 (31): 13736–13741. doi:10.1073/pnas.1001399107. PMC   2922228 . PMID   20631301.
  24. ↑ Abdelmohsen K, Gorospe M (2010). "Posttranscriptional regulation of cancer traits by HuR". Wiley Interdisciplinary Reviews. RNA. 1 (2): 214–229. doi:10.1002/wrna.4. PMC   3808850 . PMID   21935886.

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