EIF6

Last updated
EIF6
Identifiers
Aliases EIF6 , CAB, EIF3A, ITGB4BP, b(2)gcn, eIF-6, p27(BBP), p27BBP, eukaryotic translation initiation factor 6
External IDs OMIM: 602912 MGI: 1196288 HomoloGene: 7135 GeneCards: EIF6
Orthologs
SpeciesHumanMouse
Entrez

3692

16418

Ensembl

ENSG00000242372

ENSMUSG00000027613

UniProt

P56537

O55135

RefSeq (mRNA)

NM_010579

RefSeq (protein)

NP_001254739
NP_002203
NP_852131
NP_852133

NP_034709

Location (UCSC) Chr 20: 35.28 – 35.28 Mb Chr 2: 155.66 – 155.67 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Eukaryotic translation initiation factor 6 (EIF6), also known as Integrin beta 4 binding protein (ITGB4BP), is a human gene. [5]

Contents

Hemidesmosomes are structures which link the basal lamina to the intermediate filament cytoskeleton. An important functional component of hemidesmosomes is the integrin beta-4 subunit (ITGB4), a protein containing two fibronectin type III domains. The protein encoded by this gene binds to the fibronectin type III domains of ITGB4 and may help link ITGB4 to the intermediate filament cytoskeleton. The encoded protein, which is insoluble and found both in the nucleus and in the cytoplasm, can function as a translation initiation factor and catalyzes the association of the 40S and 60S ribosomal subunits along with eIF5 bound to GTP. Multiple transcript variants encoding several different isoforms have been found for this gene. [5]

EIF6 plays important roles in Eukaryotic 80S ribosome formation, cell growth and gene expression. The 80S ribosome, which can separate into 40S and 60S subunits. EIF6 helps to protect mature 60s subunit and then EIF6 should disassociate with 60s subunit so that it can binds to 40s subunit to form ribosome. Keeping in balance of EIF6 is essential for the body: few EIF6 helps synthesis of normal ribosome, while large amount of EIF6 inhibited 60s subunits bind to 40s subunits. [6]

Function

EIF6 exists both in nucleolus and cytoplasm. In the eukaryotic nucleolus, a 90S pre-ribosomal complex separate to a 60S pre-ribosomal complex and a 40S pre-ribosomal complex, which are involved in synthesis of mature ribosome. EIF6 is indispensable in 60S subunit biogenesis and deletion of EIF6 has lethal effect. The partial deletion of eIF6 results in decreasing of free 60S ribosomal subunit, which means it knocks the 40S/60S subunit ratio off balance, and limiting the speed of protein synthesis. 60S pre-ribosomal complex associated with eIF6 shuttle from nucleolus to cytoplasm and then eIF6 disassociated with pre-60S so that 60S subunit can binds to 40S subunit and continues to subsequent progress. EIF6 can act as a rate-limiting translational initiation factor, and its expression levels influence the translational rate. Few of eIF6 will small accelerate protein translation, while large of eIF6 will block translational process by inhibiting production of ribosome. [7] The activity of eIF6 also cause glycolysis and fatty acid synthesis by mRNAs' translational controlling. [8]

Structure

An x-ray crystallography-based model of eIF6 structure from S. cerevisiae 1G62 S cerevisiae.png
An x-ray crystallography-based model of eIF6 structure from S. cerevisiae

eIF6 is 245 amino acids long.

Expression

EIF6 has different level of expression in different tissue and cell. EIF6 has high level of expression in stem cells and cycling cells, while it doesn't in postmitotic cells; high level in brain and epithelia, while low level in muscle. [9]

Interactions

EIF6 has been shown to interact with FHL2, [10] ITGB4 [11] and GNB2L1. [12]

EIF6 plays important roles in 80S ribosome formation, cell growth and gene expression. [13]

Evolution

eIF6 is present in both yeast and humans, and its amino acid sequence is 77% identical between the two. [7] No duplications of eIF6, or even conserved motifs within the protein are known. [7]

History

eIF6 activity was first described by work in the early 1980s from Linda L. Spremulli's and Umadas Maitra's laboratories. [7] The gene was eventually cloned by Maitra's and Gene Carlo Marchisio's groups, both publishing their work in 1997. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Ribosome</span> Intracellular organelle consisting of RNA and protein functioning to synthesize proteins

Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis. Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to form polypeptide chains. Ribosomes consist of two major components: the small and large ribosomal subunits. Each subunit consists of one or more ribosomal RNA (rRNA) molecules and many ribosomal proteins. The ribosomes and associated molecules are also known as the translational apparatus.

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

The Kozak consensus sequence is a nucleic acid motif that functions as the protein translation initiation site in most eukaryotic mRNA transcripts. Regarded as the optimum sequence for initiating translation in eukaryotes, the sequence is an integral aspect of protein regulation and overall cellular health as well as having implications in human disease. It ensures that a protein is correctly translated from the genetic message, mediating ribosome assembly and translation initiation. A wrong start site can result in non-functional proteins. As it has become more studied, expansions of the nucleotide sequence, bases of importance, and notable exceptions have arisen. The sequence was named after the scientist who discovered it, Marilyn Kozak. Kozak discovered the sequence through a detailed analysis of DNA genomic sequences.

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">60S ribosomal protein L5</span> Protein-coding gene in the species Homo sapiens

60S ribosomal protein L5 is a protein that in humans is encoded by the RPL5 gene.

<span class="mw-page-title-main">Receptor for activated C kinase 1</span> Protein-coding gene in the species Homo sapiens

Receptor for activated C kinase 1 (RACK1), also known as guanine nucleotide-binding protein subunit beta-2-like 1 (GNB2L1), is a 35 kDa protein that in humans is encoded by the RACK1 gene.

<span class="mw-page-title-main">Integrin beta 4</span> Protein-coding gene in the species Homo sapiens

Integrin, beta 4 (ITGB4) also known as CD104, is a human gene.

<span class="mw-page-title-main">EIF2S1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 1 (eIF2α) is a protein that in humans is encoded by the EIF2S1 gene.

<span class="mw-page-title-main">EIF2S2</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 2 (eIF2β) is a protein that in humans is encoded by the EIF2S2 gene.

<span class="mw-page-title-main">EIF2S3</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 2 subunit 3 (eIF2γ) is a protein that in humans is encoded by the EIF2S3 gene.

<span class="mw-page-title-main">EIF4B</span>

Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.

<span class="mw-page-title-main">EIF2A</span>

Eukaryotic translation initiation factor 2A (eIF2A) is a protein that in humans is encoded by the EIF2A gene. The eIF2A protein is not to be confused with eIF2α, a subunit of the heterotrimeric eIF2 complex. Instead, eIF2A functions by a separate mechanism in eukaryotic translation.

<span class="mw-page-title-main">EIF3D</span>

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a protein that in humans is encoded by the EIF3D gene.

<span class="mw-page-title-main">EIF1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 1 (eIF1) is a protein that in humans is encoded by the EIF1 gene. It is related to yeast SUI1.

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.

Eukaryotic Initiation Factor 2 (eIF2) is a eukaryotic initiation factor. It is required for most forms of eukaryotic translation initiation. eIF2 mediates the binding of tRNAiMet to the ribosome in a GTP-dependent manner. eIF2 is a heterotrimer consisting of an alpha, a beta, and a gamma subunit.

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.

<span class="mw-page-title-main">Eukaryotic ribosome</span> Large and complex molecular machine

Ribosomes are a large and complex molecular machine that catalyzes the synthesis of proteins, referred to as translation. The ribosome selects aminoacylated transfer RNAs (tRNAs) based on the sequence of a protein-encoding messenger RNA (mRNA) and covalently links the amino acids into a polypeptide chain. Ribosomes from all organisms share a highly conserved catalytic center. However, the ribosomes of eukaryotes are much larger than prokaryotic ribosomes and subject to more complex regulation and biogenesis pathways. Eukaryotic ribosomes are also known as 80S ribosomes, referring to their sedimentation coefficients in Svedberg units, because they sediment faster than the prokaryotic (70S) ribosomes. Eukaryotic ribosomes have two unequal subunits, designated small subunit (40S) and large subunit (60S) according to their sedimentation coefficients. Both subunits contain dozens of ribosomal proteins arranged on a scaffold composed of ribosomal RNA (rRNA). The small subunit monitors the complementarity between tRNA anticodon and mRNA, while the large subunit catalyzes peptide bond formation.

Translational regulation refers to the control of the levels of protein synthesized from its mRNA. This regulation is vastly important to the cellular response to stressors, growth cues, and differentiation. In comparison to transcriptional regulation, it results in much more immediate cellular adjustment through direct regulation of protein concentration. The corresponding mechanisms are primarily targeted on the control of ribosome recruitment on the initiation codon, but can also involve modulation of peptide elongation, termination of protein synthesis, or ribosome biogenesis. While these general concepts are widely conserved, some of the finer details in this sort of regulation have been proven to differ between prokaryotic and eukaryotic organisms.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000242372 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000027613 - 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 "Entrez Gene: ITGB4BP integrin beta 4 binding protein".
  6. ↑ Brina D, Grosso S, Miluzio A, Biffo S (October 2011). "Translational control by 80S formation and 60S availability: the central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis". Cell Cycle. 10 (20): 3441–6. doi: 10.4161/cc.10.20.17796 . PMID   22031223.
  7. 1 2 3 4 5 Brina D, Miluzio A, Ricciardi S, Biffo S (July 2015). "eIF6 anti-association activity is required for ribosome biogenesis, translational control and tumor progression". Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms. 1849 (7): 830–5. doi:10.1016/j.bbagrm.2014.09.010. PMID   25252159.
  8. ↑ Biffo S, Manfrini N, Ricciardi S (February 2018). "Crosstalks between translation and metabolism in cancer". Current Opinion in Genetics & Development. 48: 75–81. doi:10.1016/j.gde.2017.10.011. PMID   29153483.
  9. ↑ Miluzio A, Beugnet A, Volta V, Biffo S (May 2009). "Eukaryotic initiation factor 6 mediates a continuum between 60S ribosome biogenesis and translation". EMBO Reports. 10 (5): 459–65. doi:10.1038/embor.2009.70. PMC   2680881 . PMID   19373251.
  10. ↑ Wixler V, Geerts D, Laplantine E, Westhoff D, Smyth N, Aumailley M, Sonnenberg A, Paulsson M (October 2000). "The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes". The Journal of Biological Chemistry. 275 (43): 33669–78. doi: 10.1074/jbc.M002519200 . PMID   10906324.
  11. ↑ Biffo S, Sanvito F, Costa S, Preve L, Pignatelli R, Spinardi L, Marchisio PC (November 1997). "Isolation of a novel beta4 integrin-binding protein (p27(BBP)) highly expressed in epithelial cells". The Journal of Biological Chemistry. 272 (48): 30314–21. doi: 10.1074/jbc.272.48.30314 . PMID   9374518.
  12. ↑ Ceci M, Gaviraghi C, Gorrini C, Sala LA, Offenhäuser N, Marchisio PC, Biffo S (December 2003). "Release of eIF6 (p27BBP) from the 60S subunit allows 80S ribosome assembly". Nature. 426 (6966): 579–84. Bibcode:2003Natur.426..579C. doi:10.1038/nature02160. PMID   14654845. S2CID   2431706.
  13. ↑ Brina D, Grosso S, Miluzio A, Biffo S (October 2011). "Translational control by 80S formation and 60S availability: the central role of eIF6, a rate limiting factor in cell cycle progression and tumorigenesis". Cell Cycle. 10 (20): 3441–6. doi: 10.4161/cc.10.20.17796 . PMID   22031223.

Further reading


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