DEAD box

Last updated
DEAD/DEAH box helicase
PDB 1qva EBI.jpg
Structure of the amino terminal domain of yeast initiation factor 4A. PDB 1qva [1]
Identifiers
SymbolDEAD
Pfam PF00270
Pfam clan CL0023
InterPro IPR011545
PROSITE PDOC00039
SCOP2 1qva / SCOPe / SUPFAM
CDD cd00268
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

DEAD box proteins are involved in an assortment of metabolic processes that typically involve RNAs, but in some cases also other nucleic acids. [2] They are highly conserved in nine motifs and can be found in most prokaryotes and eukaryotes, but not all. Many organisms, including humans, contain DEAD-box (SF2) helicases, which are involved in RNA metabolism. [3]

Contents

DEAD box family

DEAD box proteins were first brought to attention in the late 1980s in a study that looked at a group of NTP binding sites that were similar in sequence to the eIF4A RNA helicase sequence. [4] The results of this study showed that these proteins (p68, SrmB, MSS116, vasa, PL10, mammalian eIF4A, yeast eIF4A) involved in RNA metabolism had several common elements. [5] There were nine common sequences found to be conserved amongst the studied species, which is an important criterion of the DEAD box family. [5]

The nine conserved motif from the N-terminal to the C-terminal are named as follows: Q-motif, motif 1, motif 1a, motif 1b, motif II, motif III, motif IV, motif V, and motif VI, as shown in the figure. Motif II is also known as the Walker B motif and contains the amino acid sequence D-E-A-D (asp-glu-ala-asp), which gave this family of proteins the name “DEAD box”. [5] Motif 1, motif II, the Q motif, and motif VI are all needed for ATP binding and hydrolysis, while motifs, 1a, 1b, III, IV, and V may be involved in intramolecular rearrangements and RNA interaction. [6]

The DEAH and SKI2 families have had proteins that have been identified to be related to the DEAD box family. [7] [8] [9] These two relatives have a few particularly unique motifs[ which? ] that are conserved within their own family. [10]

DEAD box, DEAH, and the SKI2 families are collectively referred to as DExD/H proteins. [10] It is thought that each family has a specific role in RNA metabolism, for example both DEAD box and DEAH box proteins NTPase activities become stimulated by RNA, but DEAD box proteins use ATP and DEAH does not. [6]

Biological functions

DEAD box proteins are considered to be RNA helicases and many have been found to be required in cellular processes such as RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay and organellar gene expression. [10] [11] [12]

Pre-mRNA splicing

Pre-mRNA splicing requires rearrangements of five large RNP complexes, which are snRNPs U1, U2, U4, U5, and U6. DEAD box proteins are helicases that perform unwinding in an energy-dependent approach and are able to perform these snRNP rearrangements in a quick and efficient manner. [13] There are three DEAD box proteins in the yeast system, Sub2, Prp28, and Prp5, which have been proven to be required for in vivo splicing. [13] Prp5 has been shown to assist in a conformational rearrangement of U2 snRNA, which makes the branch point–recognition sequence of U2 available to bind the branch point sequence. [14] Prp28 may have a role in recognizing the 5’ splice site and does not display RNA helicase activity, suggesting that other factors must be present in order to activate Prp28. [15] DExD/H proteins have also been found to be required components in pre- mRNA splicing, in particular the DEAH proteins, Prp2, Prp16, Prp22, Prp43, and Brr213. [16] As shown in the figure, DEAD box proteins are needed in the initial steps of spliceosome formation, while DEAH box proteins are indirectly required for the transesterifications, release of the mRNA, and recycling of the spliceosome complex9.

The role of DEAD box proteins in pre-mRNA splicing. The orange text represents the DEAD box proteins. Spliceosome405.jpg
The role of DEAD box proteins in pre-mRNA splicing. The orange text represents the DEAD box proteins.

Translation initiation

The eIF4A translation initiation factor was the first DEAD box protein found to have an RNA-dependent ATPase activity. It has been proposed that this abundant protein helps in unwinding the secondary structure in the 5'-untranslated region. [17] This can inhibit the scanning process of the small ribosomal subunit, if not unwound. [17] Ded1 is another DEAD box protein that is also needed for translation initiation, but its exact role in this process is still obscure. [18] Vasa, a DEAD box protein highly related to Ded1 plays a part in translation initiation by interacting with eukaryotic initiation factor 2 (eIF2). [19]

See also

Related Research Articles

<span class="mw-page-title-main">Helicase</span> Class of enzymes to unpack an organisms genes

Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two hybridized nucleic acid strands, using energy from ATP hydrolysis. There are many helicases, representing the great variety of processes in which strand separation must be catalyzed. Approximately 1% of eukaryotic genes code for helicases.

<span class="mw-page-title-main">U4 spliceosomal RNA</span> Non-coding RNA component of the spliceosome

The U4 small nuclear Ribo-Nucleic Acid is a non-coding RNA component of the major or U2-dependent spliceosome – a eukaryotic molecular machine involved in the splicing of pre-messenger RNA (pre-mRNA). It forms a duplex with U6, and with each splicing round, it is displaced from the U6 snRNA in an ATP-dependent manner, allowing U6 to re-fold and create the active site for splicing catalysis. A recycling process involving protein Brr2 releases U4 from U6, while protein Prp24 re-anneals U4 and U6. The crystal structure of a 5′ stem-loop of U4 in complex with a binding protein has been solved.

<span class="mw-page-title-main">U5 spliceosomal RNA</span>

U5 snRNA is a small nuclear RNA (snRNA) that participates in RNA splicing as a component of the spliceosome. It forms the U5 snRNP by associating with several proteins including Prp8 - the largest and most conserved protein in the spliceosome, Brr2 - a helicase required for spliceosome activation, Snu114, and the 7 Sm proteins. U5 snRNA forms a coaxially-stacked series of helices that project into the active site of the spliceosome. Loop 1, which caps this series of helices, forms 4-5 base pairs with the 5'-exon during the two chemical reactions of splicing. This interaction appears to be especially important during step two of splicing, exon ligation.

<span class="mw-page-title-main">U6 spliceosomal RNA</span> Small nuclear RNA component of the spliceosome

U6 snRNA is the non-coding small nuclear RNA (snRNA) component of U6 snRNP, an RNA-protein complex that combines with other snRNPs, unmodified pre-mRNA, and various other proteins to assemble a spliceosome, a large RNA-protein molecular complex that catalyzes the excision of introns from pre-mRNA. Splicing, or the removal of introns, is a major aspect of post-transcriptional modification and takes place only in the nucleus of eukaryotes.

<span class="mw-page-title-main">DDX5</span> Protein-coding gene in Homo sapiens

Probable ATP-dependent RNA helicase DDX5 also known as DEAD box protein 5 or RNA helicase p68 is an enzyme that in humans is encoded by the DDX5 gene.

<span class="mw-page-title-main">DDX17</span> Protein-coding gene in the species Homo sapiens

Probable ATP-dependent RNA helicase DDX17 (p72) is an enzyme that in humans is encoded by the DDX17 gene.

<span class="mw-page-title-main">EIF4A1</span> Protein coding gene in Humans

Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.

<span class="mw-page-title-main">EIF4A3</span> Protein-coding gene in the species Homo sapiens

Eukaryotic initiation factor 4A-III is a protein that in humans is encoded by the EIF4A3 gene.

<span class="mw-page-title-main">DDX21</span> Protein-coding gene in the species Homo sapiens

Nucleolar RNA helicase 2 is an enzyme that in humans is encoded by the DDX21 gene.

<span class="mw-page-title-main">DHX38</span> Protein-coding gene in the species Homo sapiens

Pre-mRNA-splicing factor ATP-dependent RNA helicase PRP16 is an enzyme that in humans is encoded by the DHX38 gene.

<span class="mw-page-title-main">DDX23</span> Protein-coding gene in humans

Probable ATP-dependent RNA helicase DDX23 is an enzyme that in humans is encoded by the DDX23 gene.

<span class="mw-page-title-main">DHX36</span> Protein-coding gene in the species Homo sapiens

Probable ATP-dependent RNA helicase DHX36 also known as DEAH box protein 36 (DHX36) or MLE-like protein 1 (MLEL1) or G4 resolvase 1 (G4R1) or RNA helicase associated with AU-rich elements (RHAU) is an enzyme that in humans is encoded by the DHX36 gene.

<span class="mw-page-title-main">DDX42</span> Protein-coding gene in the species Homo sapiens

ATP-dependent RNA helicase DDX42 is an enzyme that in humans is encoded by the DDX42 gene.

<span class="mw-page-title-main">DHX16</span> Protein-coding gene in the species Homo sapiens

Putative pre-mRNA-splicing factor ATP-dependent RNA helicase DHX16 is an enzyme that in humans is encoded by the DHX16 gene.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

RHAU is a 114-kDa human RNA helicase of the DEAH-box family of helicases encoded by the DHX36 gene.

<span class="mw-page-title-main">Prp8</span>

Prp8 refers to both the Prp8 protein and Prp8 gene. Prp8's name originates from its involvement in pre-mRNA processing. The Prp8 protein is a large, highly conserved, and unique protein that resides in the catalytic core of the spliceosome and has been found to have a central role in molecular rearrangements that occur there. Prp8 protein is a major central component of the catalytic core in the spliceosome, and the spliceosome is responsible for splicing of precursor mRNA that contains introns and exons. Unexpressed introns are removed by the spliceosome complex in order to create a more concise mRNA transcript. Splicing is just one of many different post-transcriptional modifications that mRNA must undergo before translation. Prp8 has also been hypothesized to be a cofactor in RNA catalysis.

<span class="mw-page-title-main">DHX34</span> Protein-coding gene in the species Homo sapiens

DExH-box helicase 34 is a protein that in humans is encoded by the DHX34 gene.

<span class="mw-page-title-main">DHX8</span> Protein-coding gene in humans

DEAH-box helicase 8, is a protein that in humans is encoded by the DHX8 gene. This protein is member of the DEAH box polypeptide family. The main characteristic of this group is their conserved motif DEAH. A wide range of RNA helicases belongs to this family. Specifically, DHX8 acts as an ATP-dependent RNA helicase involved in splicing and the regulation of the releasing of spliced mRNAs from spliceosomes out of the nucleus. Published studies have shown the consequences of DHX8 mutations, some of them are critical for biological processes such as hematopoiesis and are related to some diseases.

The TREX (TRanscription-EXport) complex is a conserved eukaryotic multi-protein complex that couples mRNA transcription and nuclear export. The TREX complex travels across transcribed genes with RNA polymerase II. TREX binds mRNA and recruits transport proteins NXF1 and NXT1, which shuttle the mRNA out of the nucleus. The TREX complex plays an important role in genome stability and neurodegenerative diseases.

References

  1. ↑ Johnson, E. R.; McKay, D. B. (1999). "Crystallographic structure of the amino terminal domain of yeast initiation factor 4A, a representative DEAD-box RNA helicase". RNA. 5 (12): 1526–1534. doi:10.1017/S1355838299991410. PMC   1369875 . PMID   10606264.
  2. ↑ Takashi Kikuma; Masaya Ohtsu; Takahiko Utsugi; Shoko Koga; Kohji Okuhara; Toshihiko Eki; Fumihiro Fujimori; Yasufumi Murakami (March 2004). "Dbp9p, a Member of the DEAD Box Protein Family, Exhibits DNA Helicase Activity". J. Biol. Chem. 279 (20): 20692–20698. doi: 10.1074/jbc.M400231200 . PMID   15028736.
  3. ↑ Heung LJ, Del Poeta M (March 2005). "Unlocking the DEAD-box: a key to cryptococcal virulence?". J. Clin. Invest. 115 (3): 593–5. doi:10.1172/JCI24508. PMC   1052016 . PMID   15765144.
  4. ↑ Gorbalenya AE, Koonin EV, Donchenko AP, Blinov VM (June 1989). "Two related superfamilies of putative helicases involved in replication, recombination, repair and expression of DNA and RNA genomes". Nucleic Acids Res. 17 (12): 4713–30. doi:10.1093/nar/17.12.4713. PMC   318027 . PMID   2546125.
  5. 1 2 3 Linder, P.; Lasko, P. F.; Ashburner, M.; Leroy, P.; Nielsen, P. J.; Nishi, K.; Schnier, J.; Slonimski, P. P. (1989). "Birth of the D-E-A-D box". Nature. 337 (6203): 121–122. Bibcode:1989Natur.337..121L. doi:10.1038/337121a0. PMID   2563148. S2CID   13529955.
  6. 1 2 Tanner NK, Cordin O, Banroques J, Doère M, Linder P (January 2003). "The Q motif: a newly identified motif in DEAD box helicases may regulate ATP binding and hydrolysis". Mol. Cell. 11 (1): 127–38. doi: 10.1016/S1097-2765(03)00006-6 . PMID   12535527.
  7. ↑ Tanaka N, Schwer B (July 2005). "Characterization of the NTPase, RNA-binding, and RNA helicase activities of the DEAH-box splicing factor Prp22". Biochemistry. 44 (28): 9795–803. doi:10.1021/bi050407m. PMID   16008364.
  8. ↑ Xu J, Wu H, Zhang C, Cao Y, Wang L, Zeng L, Ye X, Wu Q, Dai J, Xie Y, Mao Y (2002). "Identification of a novel human DDX40gene, a new member of the DEAH-box protein family". J. Hum. Genet. 47 (12): 681–3. doi: 10.1007/s100380200104 . PMID   12522690.
  9. ↑ Wang L, Lewis MS, Johnson AW (August 2005). "Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p". RNA. 11 (8): 1291–302. doi:10.1261/rna.2060405. PMC   1370812 . PMID   16043509.
  10. 1 2 3 de la Cruz J, Kressler D, Linder P (May 1999). "Unwinding RNA in Saccharomyces cerevisiae: DEAD-box proteins and related families". Trends Biochem. Sci. 24 (5): 192–8. doi:10.1016/S0968-0004(99)01376-6. PMID   10322435.
  11. ↑ Aubourg S, Kreis M, Lecharny A (January 1999). "The DEAD box RNA helicase family in Arabidopsis thaliana". Nucleic Acids Res. 27 (2): 628–36. doi:10.1093/nar/27.2.628. PMC   148225 . PMID   9862990.
  12. ↑ Staley JP, Guthrie C (February 1998). "Mechanical devices of the spliceosome: motors, clocks, springs, and things". Cell. 92 (3): 315–26. doi: 10.1016/S0092-8674(00)80925-3 . PMID   9476892. S2CID   6208113.
  13. 1 2 Linder P (2006). "Dead-box proteins: a family affair—active and passive players in RNP-remodeling". Nucleic Acids Res. 34 (15): 4168–80. doi:10.1093/nar/gkl468. PMC   1616962 . PMID   16936318.
  14. ↑ Ghetti A, Company M, Abelson J (April 1995). "Specificity of Prp24 binding to RNA: a role for Prp24 in the dynamic interaction of U4 and U6 snRNAs". RNA. 1 (2): 132–45. PMC   1369067 . PMID   7585243.
  15. ↑ Strauss EJ, Guthrie C (August 1994). "PRP28, a 'DEAD-box' protein, is required for the first step of mRNA splicing in vitro". Nucleic Acids Res. 22 (15): 3187–93. doi:10.1093/nar/22.15.3187. PMC   310295 . PMID   7520570.
  16. ↑ Silverman E, Edwalds-Gilbert G, Lin RJ (July 2003). "DExD/H-box proteins and their partners: helping RNA helicases unwind". Gene. 312: 1–16. doi:10.1016/S0378-1119(03)00626-7. PMID   12909336.
  17. 1 2 Sonenberg N (1988). Cap-binding proteins of eukaryotic messenger RNA: functions in initiation and control of translation. Progress in Nucleic Acid Research and Molecular Biology. Vol. 35. pp. 173–207. doi:10.1016/S0079-6603(08)60614-5. ISBN   978-0-12-540035-0. PMID   3065823.
  18. ↑ Berthelot K, Muldoon M, Rajkowitsch L, Hughes J, McCarthy JE (February 2004). "Dynamics and processivity of 40S ribosome scanning on mRNA in yeast". Mol. Microbiol. 51 (4): 987–1001. doi: 10.1046/j.1365-2958.2003.03898.x . PMID   14763975.
  19. ↑ Carrera P, Johnstone O, Nakamura A, Casanova J, Jäckle H, Lasko P (January 2000). "VASA mediates translation through interaction with a Drosophila yIF2 homolog". Mol. Cell. 5 (1): 181–7. doi:10.1016/S1097-2765(00)80414-1. hdl: 11858/00-001M-0000-0012-F80E-6 . PMID   10678180.
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