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Basic leucine zipper and W2 domain-containing protein 2

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Basic Leucine Zipper and W2 Domain-Containing Protein 2 is a protein that is encoded by the BZW2 gene.[5][6] It is a eukaryotic translation factor[vague] found in species up to bacteria. In animals, it is localized in the cytoplasm and expressed ubiquitously throughout the body. The heart, placenta, skeletal muscle, and hippocampus show higher expression. In various cancers, upregulation tends to lead to higher severity and mortality. It has been found to interact with SARS-CoV-2.

BZW2
Identifiers
AliasesBZW2, MST017, MSTP017, HSPC028, basic leucine zipper and W2 domains 2, 5MP1
External IDsMGI: 1914162; HomoloGene: 8530; GeneCards: BZW2; OMA:BZW2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

28969

66912

Ensembl

ENSG00000136261

ENSMUSG00000020547

UniProt

Q9Y6E2

Q91VK1

RefSeq (mRNA)

NM_001159767
NM_014038
NM_001362717
NM_001362718
NM_001362719

NM_025840

RefSeq (protein)

NP_001153239
NP_054757
NP_001349646
NP_001349647
NP_001349648

NP_080116

Location (UCSC)Chr 7: 16.65 – 16.71 MbChr 12: 36.14 – 36.21 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene

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BZW2 is known as Basic Leucine Zipper W2 Domain-Containing Protein 2, MST017, MSTP017, 5MP1, Eukaryotic Translation Factor 5, and HSPC028.[7] It is located on chromosome 7 at p21.1 on the plus strand. The gene spans 60,389 base pairs, at coordinates 16,583,248 – 16,804,999. There are 12 exons.

Protein

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There are two known isoforms of BZW2. Isoform 1 is 419 amino acids long and is the most abundant form. Isoform 2 is 225 amino acids, containing only 11 exons and a shorter N-terminus.[7]

The coded protein is 419 amino acids long and weighs 48.3 kDa.[8] As described in the name, the protein contains a leucine-zipper motif. Four “L……” repeats are present in the beginning, giving rise to the characteristic leucine zipper helix within the 3D structure. An eIF5C domain follows the leucine motif, which is a part of proteins that are important for strict regulation of cellular processes.[9]

The amino acid composition of BZW2 has a higher amount of lysines and a lower amount of prolines in humans but a higher glutamic acid composition in its orthologs.[10] The human BZW2 protein has an overall charge of -3 which can go down to -9 in orthologs. There are no significant charge clusters. There is also a KELQ repeat that has remained conserved in animals.

 
Sequence of BZW2 is shown with positions of spacing information, charge clusters, and repeats.

The secondary structure contains a majority of alpha helices.[11] There are 19 alpha helices in all orthologs, except for two additional beta sheets which are absent in humans. The tertiary structure forms a repeated fold of alpha-helices, a structure that is conserved through bacteria.

 
BZW2 structure from Phyre2 colored from N-terminus (red) to C-terminus (blue).

Regulation

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Gene-level

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There are three known promoters for BZW2.[12] It is regulated by numerous transcription factors, including an estrogen receptor transcription factor (ESR2, ES3), leucine zipper transcription factor (RRFIP1), and Y sex-determining transcription factors (SRY). With these transcription factors, BZW2 has regulated expression in organs that contribute to cellular functions. The Y sex-determining transcription factor works to regulate BZW2 expression in the testis. Throughout the body, BZW2 is ubiquitously expressed within tissues. There is elevated mRNA abundance in the heart, placenta, and skeletal muscle.  

Transcript-level

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There are four major stem loops in the 5’ untranslated and four in the 3’ untranslated region that function in transcript-level regulation.[13]

Protein-level

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BZW2 has multiple phosphorylation, acetylation, glycosylation, SUMOylation, and glycation sites for regulation.[14] Since upregulation of BZW2 leads to disrupted cellular processes and severe cancer forms, post-translational modifications are needed to keep the gene highly regulated. The protein is localized within the cytoplasm and has no likely or confirmed nuclear or mitochondrial target peptides.

 
Schematic of the post-translational modification locations on the BZW2 protein.

Evolution

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BZW2 has a single paralog, BZW1 which is conserved up to plants.[15] There are BZW2 orthologs up to a couple species of bacteria. The most distant ortholog was Microbacterium arborescens. BZW2 contains an eIF5C domain which is also present in eIF2BE, eIF4G, eIF5, and a GAP protein specific for eIF2.[16]

Select BZW2 Orthologs
Species Common Name Order Million years since divergence from humans Similarity % Identity %
Homo sapiens Human Primates 0 100 100
Mus musculus Mouse Rodentia 29 100 99
Phocoena sinus Vaquita Artiodactyla 94 99 99
Ornithorhynchus anatinus Duckbill platypus Monotremata 180 97 95
Columba livia Rock pigeon Columbiformes 318 95 90
Pantherophis guttatus Corn snake Squamata 318 97 92
Terrapene carolina triunguis Three-toed box turtle Testudines 318 97 92
Pygoscelis adeliae Adelie penguin Spehnisciformes 318 96 97
Xenopus tropicalis Western clawed frog Anura 419 97 90
Danio rerio Zebrafish Cypriniformes 433 84 95
Ambylraia radiata Thorny skate Raiiformes 465 96 86
Petromyzon marinus Sea lamprey Petromyzontiformes 599 86 73
Acanthaster planci Crown-of-thorns starfish Valvatida 627 69 51
Drosophila melanogaster Fruit fly Diptera 736 72 49
Coptotermes formosanus Formosan termite Blattodea 736 69 51
Gigaspora rosea NA Diversisporales 1017 62 38
Rhizophagus irregularis NA Glomerales 1017 62 38
Camellia sinensis Tea plant Ericales 1275 55 35
Rhodamnia argentea Malletwood Myrtales 1275 69 47
Microbacterium arborescens NA Actinomycetales 4090 30 20
Leptospira ognonensis NA Leptospirales 4090 51 37
Aeromonas veronii NA Aeromondales 4090 87 69
 
A phylogenetic tree illustrates the BZW2 sequence relationships between orthologs.

Compared to Cytochrome C, a quickly diverging protein, and Fibrinogen, a slowly diverging protein, BZW2 has had slow corrected divergence over time, illustrating conservation and protein importance.

 
BZW2 corrected divergence over million years diverged from humans,

Interactions

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BZW2 is known to interact with:

EIF2S2 and ORF4 work to synthesize and replicate BZW2.[17] PSTPIP1 and NEK4 are regulatory proteins that help in the functionality of BZW2.[18][19] SNW1, a spliceosome protein, splices BZW2 mRNA variants.[20] The protein rep is part of SARS-CoV-2 virus and inhibits translation of BZW2.[21]

Clinical significance

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Cancer

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BZW2 has been studied to determine its role in multiple cancers. Overall, the studies all showed that upregulation of BZW2 lead to more severe forms of cancer, higher rate of mortality, and increased likeliness of reoccurrence.

A 2019 study focused on the effect of BZW2 in colorectal cancer.[22] It found that upregulation of BZW2 promoted tumor growth and had a downstream upregulation effect on c-Myc, a proto-oncogene. A second study from 2020 determined this upregulation also had a positive effect on the activation of the ERK/MAPK pathway. [23]

In hepatocellular carcinoma, osteosarcoma, lung adenocarcinoma, and muscle-invasive bladder cancer, overexpression of BZW2 lead to overactivation of the AKT/mTOR signaling pathway by increasing phosphorylation of AKT and mTOR.[24][25][26][27] The AKT/mTOR pathway is an important intracellular signaling pathway that regulates the cell cycle. When the pathway activity is increased, cells proliferated at a higher rate and apoptosis decreases, leading to tumor growth.

SARS-CoV-2

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BZW2 interacts with the nsp8 protein of SARS-CoV-2. nsp8 dimerizes and forms a supercomplex which works to repress the translation of BZW2.

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136261 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020547 – 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. ^ Zhang QH, Ye M, Wu XY, Ren SX, Zhao M, Zhao CJ, et al. (October 2000). "Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells". Genome Research. 10 (10): 1546–60. doi:10.1101/gr.140200. PMC 310934. PMID 11042152.
  6. ^ "Entrez Gene: BZW2 basic leucine zipper and W2 domains 2".
  7. ^ a b "BZW2 basic leucine zipper and W2 domains 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2020-07-31.
  8. ^ "BZW2 Antibody (PA5-21808)". www.thermofisher.com. Retrieved 2020-07-31.
  9. ^ "InterPro". www.ebi.ac.uk. Retrieved 2020-08-01.
  10. ^ Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, et al. (July 2019). "The EMBL-EBI search and sequence analysis tools APIs in 2019". Nucleic Acids Research. 47 (W1): W636–W641. doi:10.1093/nar/gkz268. PMC 6602479. PMID 30976793.
  11. ^ Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ (June 2015). "The Phyre2 web portal for protein modeling, prediction and analysis". Nature Protocols. 10 (6): 845–58. doi:10.1038/nprot.2015.053. PMC 5298202. PMID 25950237.
  12. ^ "Genomatix - NGS Data Analysis & Personalized Medicine". www.genomatix.de. Archived from the original on 2001-02-24. Retrieved 2020-07-31.
  13. ^ Zuker M (July 2003). "Mfold web server for nucleic acid folding and hybridization prediction". Nucleic Acids Research. 31 (13): 3406–15. doi:10.1093/nar/gkg595. PMC 169194. PMID 12824337.
  14. ^ "BZW2 (human)". www.phosphosite.org. Retrieved 2020-07-31.
  15. ^ "Protein BLAST: search protein databases using a protein query". blast.ncbi.nlm.nih.gov. Retrieved 2020-07-31.
  16. ^ Koonin EV (August 1995). "Multidomain organization of eukaryotic guanine nucleotide exchange translation initiation factor eIF-2B subunits revealed by analysis of conserved sequence motifs". Protein Science. 4 (8): 1608–17. doi:10.1002/pro.5560040819. PMC 2143190. PMID 8520487.
  17. ^ "Eukaryotic translation initiation factor 2 subunit 2". Uniprot. Archived from the original on 2011-05-03.
  18. ^ "Proline-serine-threonine phosphatase-interacting protein 1". Uniprot. Archived from the original on 2009-09-25.
  19. ^ "Serine/threonine-protein kinase Nek4". Uniprot. Archived from the original on 2011-04-11.
  20. ^ "SNW domain-containing protein 1". Uniprot. Archived from the original on 2011-04-12.
  21. ^ "Replicase polyprotein 1ab". Uniprot. Archived from the original on 2020-05-16.
  22. ^ Sato K, Masuda T, Hu Q, Tobo T, Gillaspie S, Niida A, et al. (June 2019). "Novel oncogene 5MP1 reprograms c-Myc translation initiation to drive malignant phenotypes in colorectal cancer". eBioMedicine. 44: 387–402. doi:10.1016/j.ebiom.2019.05.058. PMC 6606960. PMID 31175057.
  23. ^ Huang L, Chen S, Fan H, Ai F, Sheng W (May 2020). "BZW2 promotes the malignant progression of colorectal cancer via activating the ERK/MAPK pathway". Journal of Cellular Physiology. 235 (5): 4834–4842. doi:10.1002/jcp.29361. PMID 31643092. S2CID 204850013.
  24. ^ Cheng DD, Li SJ, Zhu B, Yuan T, Yang QC, Fan CY (October 2017). "Downregulation of BZW2 inhibits osteosarcoma cell growth by inactivating the Akt/mTOR signaling pathway". Oncology Reports. 38 (4): 2116–2122. doi:10.3892/or.2017.5890. PMC 5652953. PMID 28791373.
  25. ^ Jin X, Liao M, Zhang L, Yang M, Zhao J (February 2019). "Role of the novel gene BZW2 in the development of hepatocellular carcinoma". Journal of Cellular Physiology. 234 (9): 16592–16600. doi:10.1002/jcp.28331. PMID 30805927. S2CID 73473337.
  26. ^ Dong Y, Liu Y, Bai H, Jiao S (April 2019). "Systematic assessment of the clinicopathological prognostic significance of tissue cytokine expression for lung adenocarcinoma based on integrative analysis of TCGA data". Scientific Reports. 9 (1): 6301. Bibcode:2019NatSR...9.6301D. doi:10.1038/s41598-019-42345-0. PMC 6474906. PMID 31004093.
  27. ^ Gao H, Yu G, Zhang X, Yu S, Sun Y, Li Y (June 2019). "BZW2 gene knockdown induces cell growth inhibition, G1 arrest and apoptosis in muscle-invasive bladder cancers: A microarray pathway analysis". Journal of Cellular and Molecular Medicine. 23 (6): 3905–3915. doi:10.1111/jcmm.14266. PMC 6533564. PMID 30932331.

Further reading

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