Nuclear cap-binding protein complex

Last updated
nuclear cap-binding protein complex
1H6K.pdb.jpg
Crystal structure of the human nuclear cap-binding complex. [1]
Identifiers
SymbolNCBP1
Alt. symbolsNCBP
NCBI gene 4686
HGNC 7658
RefSeq NM_002486
Other data
Locus Chr. 9 q34.1
Nuclear cap binding protein subunit 2, 20kDa
Identifiers
SymbolNCBP2
NCBI gene 22916
HGNC 7659
OMIM 605133
RefSeq NM_007362
UniProt P52298
Other data
Locus Chr. 3 q29
Search for
Structures Swiss-model
Domains InterPro

Nuclear cap-binding protein complex is a RNA-binding protein which binds to the 5' cap of pre-mRNA. The cap and nuclear cap-binding protein have many functions in mRNA biogenesis including splicing, 3'-end formation by stabilizing the interaction of the 3'-end processing machinery, nuclear export and protection of the transcripts from nuclease degradation. [2] During mRNA export, the nuclear cap-binding protein complex recruits ribosomes to begin the pioneer round of translation. [3] When RNA is exported to the cytoplasm the nuclear cap-binding protein complex is replaced by cytoplasmic cap binding complex. The nuclear cap-binding complex is a functional heterodimer and composed of Cbc1/Cbc2 in yeast and CBP20/CBP80 in multicellular eukaryotes. Human nuclear cap-binding protein complex shows the large subunit, CBP80 consists of 757 amino acid residues. Its secondary structure contains approximately sixty percent of helical and one percent of beta sheet in the strand. The small subunit, CBP20 has 98 amino acid residues. Its secondary structure contains approximately twenty percent of helical and twenty-four percent of beta sheet in the strand. [1] Human nuclear cap-binding protein complex plays important role in the maturation of pre-mRNA and in uracil-rich small nuclear RNA. [4]

Contents

Nuclear cap-binding protein complex Cap-binding complex 1H2T.png
Nuclear cap-binding protein complex

Structure

In eukaryotes, the nuclear cap-binding protein complex is a heterodimer that is composed of two subunits, CBP80 and CBP20. The CBP20 subunit binds to the cap while CBP80 ensures high-affinity cap binding. The CBP80 is a superhelical structure and it is made up of three domains that are connected by two linkers. Domain 1 of CBP80 plays an important role in cap-dependent translation of mRNA. CBP80 ensures high-affinity cap binding by stabilizing the N-terminal loop of CBP20 which locks the cap-binding protein complex into a high-affinity cap-binding state. The CBP20 is composed of the C-terminus, the RNP domain, and the N-terminus. The CBP20 goes through a conformational change when it is bound to the pre-mRNA, it transitions from an open state to a closed, folded state. The conformational change results from a hinge-like motion of the N terminus from the alpha helixes in the α2–α3 loop towards the β-sheets. There is little change in the RNP region of CBP20 in the bound and un-bound states, which indicates this region may act as the initial binding site for the cap structure. [5]

Role in translation

In mammals, the nuclear cap-binding complex can drive and is necessary to initiate the translation of mRNA through cap-binding complex-dependent translation. The cap-binding complex-dependent translation has an important role in protein synthesis and mRNA surveillance. The translation of nuclear cap-binding complex-bound mRNA serves to control the quality of gene expression, while the translation of eIF4E-bound mRNAs serves to produce the majority of proteins. [6] However, both of these mRNAs use many of the same translation initiation factors; such as PABPC1, eIF4G, eIF3, eIF4B, eIF4A and eIF2. [6] [7] Translation is started when the 40S ribosomal subunit binds to the nuclear cap-binding protein complex and finds the start codon through a scanning complex in the 5' to 3' direction. The first round of translation is primarily mediated by the nuclear cap-binding protein complex, since freshly synthesized mRNA have a 5'-end cap that is bound to the nuclear cap-binding protein complex. [8] The cap-binding site of the nuclear cap-binding protein complex needs to be regulated so the pre-mRNA can lose this complex and become mature RNA. [5] In some instances, the nuclear cap-binding complex is replaced by eIF4E in a translation-independent manner in order to continue translation of the mRNA. To finish creating mature mRNA the nuclear cap-binding protein complex is bound to a 5’-m7GpppN cap structure, the cap structure then binds to the eukaryotic translation initiation factor 4E (eIF4E) which directs steady-state rounds of mRNA translation. This process of translation changes from cap-binding complex dependent translation to eIF4E-dependent translation. [8]

Role in quality assurance

Quality assurance during pioneer round

The nuclear cap-binding protein complex supports the pioneer round of mRNA translation, this pioneer round is important for mRNA quality control. The pioneer round consists of the loading of one or more ribosomes, depending on the efficacy of translation initiation and the length of the open translational reading frame in order to remove premature stop codons. [6] [9] It is thought that the CBP80 subunit could be an effector of the pioneer stage since the binding of the nuclear cap-binding protein complex to the cap site is stimulated by growth factors during the G1/S phase. [7]

Quality assurance through nonsense-mediated decay

The nuclear cap-binding complex has a larger role in mRNA quality control than it does in actual protein synthesis. [8] One of the ways that it does this quality control is through nonsense-mediated decay. Nonsense-mediated decay is when faulty mRNA's that have stop codons too early are recognized by the SURF complex and down-regulated. [3] [7] Nonsense-mediated decay is thought to be triggered when the first ribosome that translated a new nuclear cap-binding protein complex-bound mRNA has a stop codon that is found more than 50-55 nucleotides upstream of an exon-junction complex-bearing exon-exon junction. [7] The nuclear cap-binding complex is crucial to nonsense-mediated decay because it makes up the mRNP that harbors the exon-junction complex and because CBP80 directly interacts with the nonsense-mediated decay factor, up-frameshift 1 (UPF1) which amplifies the efficiency of the whole process. The nuclear cap-binding complex is largely important in this process as it has been found that nonsense-mediated decay is only found in nuclear cap-binding complex-bound mRNA. [6]

Stress conditions

Nuclear cap-binding complex-dependent translation was found to be relatively unaffected by certain environmental stressors such as in hypoxic, heat shock, or serum-starved conditions, while eIF4E-dependent translation was found to be greatly affected. [7] [8] In heat shock and serum-starved conditions nuclear cap-binding complex-dependent translation is greatly favored over eIF4E-dependent translation. [10] [11] This could mean that nuclear cap-binding complex-dependent translation has the potential to support translation in high stress environments. [8]

Related Research Articles

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

SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respectively. SR proteins are ~200-600 amino acids in length and composed of two domains, the RNA recognition motif (RRM) region and the RS domain. SR proteins are more commonly found in the nucleus than the cytoplasm, but several SR proteins are known to shuttle between the nucleus and the cytoplasm.

Ribosome shunting is a mechanism of translation initiation in which ribosomes bypass, or "shunt over", parts of the 5' untranslated region to reach the start codon. However, a benefit of ribosomal shunting is that it can translate backwards allowing more information to be stored than usual in an mRNA molecule. Some viral RNAs have been shown to use ribosome shunting as a more efficient form of translation during certain stages of viral life cycle or when translation initiation factors are scarce. Some viruses known to use this mechanism include adenovirus, Sendai virus, human papillomavirus, duck hepatitis B pararetrovirus, rice tungro bacilliform viruses, and cauliflower mosaic virus. In these viruses the ribosome is directly translocated from the upstream initiation complex to the start codon (AUG) without the need to unwind RNA secondary structures.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

<span class="mw-page-title-main">Nonsense-mediated decay</span> Elimination of mRNA with premature stop codons in eukaryotes

Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberrant mRNAs could, in some cases, lead to deleterious gain-of-function or dominant-negative activity of the resulting proteins.

In molecular biology, initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

Eukaryotic initiation factors (eIFs) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. These proteins help stabilize the formation of ribosomal preinitiation complexes around the start codon and are an important input for post-transcription gene regulation. Several initiation factors form a complex with the small 40S ribosomal subunit and Met-tRNAiMet called the 43S preinitiation complex. Additional factors of the eIF4F complex recruit the 43S PIC to the five-prime cap structure of the mRNA, from which the 43S particle scans 5'-->3' along the mRNA to reach an AUG start codon. Recognition of the start codon by the Met-tRNAiMet promotes gated phosphate and eIF1 release to form the 48S preinitiation complex, followed by large 60S ribosomal subunit recruitment to form the 80S ribosome. There exist many more eukaryotic initiation factors than prokaryotic initiation factors, reflecting the greater biological complexity of eukaryotic translation. There are at least twelve eukaryotic initiation factors, composed of many more polypeptides, and these are described below.

<span class="mw-page-title-main">Eukaryotic translation termination factor 1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation termination factor1 (eRF1), also referred to as TB3-1 or SUP45L1, is a protein that is encoded by the ERF1 gene. In Eukaryotes, eRF1 is an essential protein involved in stop codon recognition in translation, termination of translation, and nonsense mediated mRNA decay via the SURF complex.

<span class="mw-page-title-main">Hepatitis C virus internal ribosome entry site</span>

The Hepatitis C virus internal ribosome entry site, or HCV IRES, is an RNA structure within the 5'UTR of the HCV genome that mediates cap-independent translation initiation.

<span class="mw-page-title-main">Cap binding complex</span> Formation on 5 ends of mRNAs

The 5' cap of eukaryotic messenger RNA is bound at all times by various cap-binding complexes (CBCs).

<span class="mw-page-title-main">EIF4E</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene.

<span class="mw-page-title-main">RBM8A</span> Protein-coding gene in the species Homo sapiens

RNA-binding protein 8A is a protein that in humans is encoded by the RBM8A gene.

<span class="mw-page-title-main">UPF1</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 1 is a protein that in humans is encoded by the UPF1 gene.

<span class="mw-page-title-main">RNPS1</span> Protein-coding gene in the species Homo sapiens

RNA-binding protein with serine-rich domain 1 is a protein that in humans is encoded by the RNPS1 gene.

<span class="mw-page-title-main">UPF2</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 2 is a protein that in humans is encoded by the UPF2 gene.

<span class="mw-page-title-main">UPF3B</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3B is a protein that in humans is encoded by the UPF3B gene.

<span class="mw-page-title-main">UPF3A</span> Protein-coding gene in the species Homo sapiens

Regulator of nonsense transcripts 3A is a protein that in humans is encoded by the UPF3A gene.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

mRNA surveillance mechanisms are pathways utilized by organisms to ensure fidelity and quality of messenger RNA (mRNA) molecules. There are a number of surveillance mechanisms present within cells. These mechanisms function at various steps of the mRNA biogenesis pathway to detect and degrade transcripts that have not properly been processed.

<span class="mw-page-title-main">Exon junction complex</span> Protein complex assembled on mRNA

An exon junction complex (EJC) is a protein complex which forms on a pre-messenger RNA strand at the junction of two exons which have been joined together during RNA splicing. The EJC has major influences on translation, surveillance, localization of the spliced mRNA, and m6A methylation. It is first deposited onto mRNA during splicing and is then transported into the cytoplasm. There it plays a major role in post-transcriptional regulation of mRNA. It is believed that exon junction complexes provide a position-specific memory of the splicing event. The EJC consists of a stable heterotetramer core, which serves as a binding platform for other factors necessary for the mRNA pathway. The core of the EJC contains the protein eukaryotic initiation factor 4A-III bound to an adenosine triphosphate (ATP) analog, as well as the additional proteins Magoh and Y14. The binding of these proteins to nuclear speckled domains has been measured recently and it may be regulated by PI3K/AKT/mTOR signaling pathways. In order for the binding of the complex to the mRNA to occur, the eIF4AIII factor is inhibited, stopping the hydrolysis of ATP. This recognizes EJC as an ATP dependent complex. EJC also interacts with a large number of additional proteins; most notably SR proteins. These interactions are suggested to be important for mRNA compaction. The role of EJC in mRNA export is controversial.

<span class="mw-page-title-main">Eukaryotic initiation factor 4F</span> Multiprotein complex used in gene expression

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.

References

  1. 1 2 PDB: 1H6K ​; Mazza C, Ohno M, Segref A, Mattaj IW, Cusack S (August 2001). "Crystal structure of the human nuclear cap binding complex". Molecular Cell. 8 (2): 383–396. doi: 10.1016/S1097-2765(01)00299-4 . PMID   11545740.
  2. ↑ Raczynska KD, Simpson CG, Ciesiolka A, Szewc L, Lewandowska D, McNicol J, et al. (January 2010). "Involvement of the nuclear cap-binding protein complex in alternative splicing in Arabidopsis thaliana". Nucleic Acids Research. 38 (1): 265–278. doi:10.1093/nar/gkp869. PMC   2800227 . PMID   19864257.
  3. 1 2 Choe J, Oh N, Park S, Lee YK, Song OK, Locker N, et al. (May 2012). "Translation initiation on mRNAs bound by nuclear cap-binding protein complex CBP80/20 requires interaction between CBP80/20-dependent translation initiation factor and eukaryotic translation initiation factor 3g". The Journal of Biological Chemistry. 287 (22): 18500–18509. doi: 10.1074/jbc.M111.327528 . PMC   3365721 . PMID   22493286.
  4. ↑ Mazza C, Segref A, Mattaj IW, Cusack S (October 2002). "Large-scale induced fit recognition of an m(7)GpppG cap analogue by the human nuclear cap-binding complex". The EMBO Journal. 21 (20): 5548–5557. doi:10.1093/emboj/cdf538. PMC   129070 . PMID   12374755.
  5. 1 2 Calero G, Wilson KF, Ly T, Rios-Steiner JL, Clardy JC, Cerione RA (December 2002). "Structural basis of m7GpppG binding to the nuclear cap-binding protein complex". Nature Structural Biology. 9 (12): 912–917. doi:10.1038/nsb874. PMID   12434151. S2CID   37901456.
  6. 1 2 3 4 Isken O, Maquat LE (September 2008). "The multiple lives of NMD factors: balancing roles in gene and genome regulation". Nature Reviews. Genetics. 9 (9): 699–712. doi:10.1038/nrg2402. PMC   3711694 . PMID   18679436.
  7. 1 2 3 4 5 Maquat LE, Tarn WY, Isken O (August 2010). "The pioneer round of translation: features and functions". Cell. 142 (3): 368–374. doi:10.1016/j.cell.2010.07.022. PMC   2950652 . PMID   20691898.
  8. 1 2 3 4 5 Ryu I, Kim YK (April 2017). "Translation initiation mediated by nuclear cap-binding protein complex". BMB Reports. 50 (4): 186–193. doi:10.5483/bmbrep.2017.50.4.007. PMC   5437962 . PMID   28088948.
  9. ↑ Isken O, Kim YK, Hosoda N, Mayeur GL, Hershey JW, Maquat LE (April 2008). "Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay". Cell. 133 (2): 314–327. doi:10.1016/j.cell.2008.02.030. PMC   4193665 . PMID   18423202.
  10. ↑ Oh N, Kim KM, Cho H, Choe J, Kim YK (October 2007). "Pioneer round of translation occurs during serum starvation". Biochemical and Biophysical Research Communications. 362 (1): 145–151. doi:10.1016/j.bbrc.2007.07.169. PMID   17693387.
  11. ↑ Marín-Vinader L, van Genesen ST, Lubsen NH (November 2006). "mRNA made during heat shock enters the first round of translation". Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression. 1759 (11–12): 535–542. doi:10.1016/j.bbaexp.2006.10.003. PMID   17118471.
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