Wikipedia

Draft:WDR88

WD repeat containing protein 88 (WDR88) is a protein, which in humans, is encoded by the gene WDR88[1]. It consists of 7 WD40 repeats, which form a 7-bladed beta propeller. Mutations within the WDR88 gene are associated with a variety of cancers, as well as schizophrenia and fungal infections.

Coding Sequence Mutations
Type Position Base Change Amino Acid Change Associations rsID Label
Missense 103 365A-->G H-->Q Schizophrenia exm1453333 VarA
Missense 166 496G-->A D-->N 1483589630
Missense 172 514T-->C W-->R 1973547431 VarB
Missense 173 517G-->C D-->H 2145383159
Missense 195 583T-->G S-->A 964934511
Missense 198 593G-->A G-->D 1973572567
Missense 229 687C-->A, 687C-->T H-->Q, = 1390996134
Missense 236 707G-->A C-->Y 1973627073 VarC
Missense 238 712T-->C F-->L 1315930267
Missense 258 772G-->C D-->V 1350318862
Missense 285 854G-->A G-->D 1973735806
Nonsense (stop gain) 293 878G-->A, 879G-->A W-->Ter 766698986, 1454699628 VarD/E
Missense 300 898T-->C W-->R 1973736716
Nonsense (stop gain) 300 900G-->A W-->Ter 1973736779 VarF
Missense 320 958C-->G, 958C-->T H-->D, Y 571091956
Missense 322 964G-->A G-->S 938493076 VarG
Missense 327 979T-->C, 979T-->G C-->R, G 916309262
Missense 332 995A-->G D-->G 1973739195
Missense 339 1016G-->A G-->R, E 753069912, 138717522
Missense 342 1024G-->C D-->H 1973845950
Missense 348 1043G-->T W-->L 200178208
Missense 362 1085A-->G H-->R 1213339071
Missense 368 1103A-->G D-->R 1973916950 VarH
Missense 372 1115G-->T S-->I 11668547
Missense 378 1188C-->T I-->F Schizophrenia exm1453382 VarI
Missense 383 1148A-->G K-->R 768741120
Missense 386 1156A-->C T-->P 751290834 VarJ
Missense 390 1168T-->C, 1168T-->G W-->R, G 1291251743
Missense 424 1328C>T I-->A, G Candidiasis rs10422015
Missense 437 1311C-->G, 1311C-->T C-->W, = 760463708
Nonsense (stop lost) 473 1417T-->C, G Ter-->R, G 760940871 VarK
Nonsense (stop lost) 473 1419A-->G Ter -->W 146733199 VarL

Gene

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WDR88 gene on human chromosome 19. Image courtesy of GeneCards.[2]

The WDR88 gene is on chromosome 19 at position 19q13.11 on the plus strand[3]. The gene is encoded from position 33,132,114 to 33,175,799[4]. It has 11 exons, and is approximately 1702 base pairs long[5]. Other genes in the gene neighborhood include: RHPN2 (rhophilin rho GTPase binding protein 2), LRP3 (low density lipoprotein receptor-related protein 3), SLC7A10 (solute carrier family 7 membrane 10), and GPATCH1 (G-patch domain containing 1)[6]. The WDR88 gene may also be referred to as PQWD (PQQ repeat containing and WD repeat containing gene).

Transcripts

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The gene WDR88 has 3 isoforms[7]. The splice variants of the WDR88 transcript vary according to their first and last exon and their last two exons. This isoform (aAug10) has an mRNA sequence of 1702 nucleotides.

Comparison of the 3 WDR88 isoforms
mRNA Variant Gene Length Protein Length 5' UTR 3' UTR
aAug10 1702 472 56 227
bAug10 1835 426 78 476
cAug10-unspliced 561 121 - 195

Tissue Expression

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WDR88 RNA expression in 20 human tissues. WDR88 is abundance is relevant in thymus, prostate, and salivary gland.

WDR88 RNA is expressed lowly and ubiquitously in most tissue types. It is expressed in slightly higher levels in the prostate, thyroid, thymus, and salivary gland[8][9]. Its presence in these tissues may relate to associated diseases- WDR88 has been associated with prostate cancer, as well as an increased susceptibility of Candidiasis (which may also be associated with cancer of the salivary gland). Thymus cell dysfunction may also lead to cancer (including prostate cancer)[10].

Other tissues with moderate expression include the heart, skeletal muscle, brain, kidney, lymph nodes, and ovaries[11].

Protein

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The WDR88 protein is a nuclear protein[12]. The protein is 472 amino acids long and has a calculated molecular weight of 53kDa. Its isoelectric point is approximately a pH of 7.0[13][14]. In addition, there is an increased abundance of cysteine, aspartic acid, and serine residues[15]. Its increased abundance of serine may contribute to its ability to be hyperphosphorylated. Human WDR88 displays a somewhat similar and isoelectric point to selected orthologs.

Molecular Characteristics by Species
Species Type Common Name Scientific Name Molecular Weight (kDa) Isoelectric Point
Mammals Human Homo sapiens 53 7.0
Mammals Koala Phascolarctos cinereus 48 6.3
Mammals Large flying fox bat Pteropus vampyrus 55 6.7
Mammals Small madagascar hedgehog Echinops telfairi 54 8.9
Mammals Australian echidna Tachyglossus aculeatus 47 8.2
Mammals Cattle Bos taurus 63 6.7
Birds South African ostrich Struthio camelus australis 44 7.2
Birds Barn owl Tyto alba 44 5.9
Birds Emperor penguin Aptenodytes forsteri 52 6.5
Reptiles Chinese soft shelled turtle Pelodiscus sinensis 46 5.9
Reptiles Australian saltwater crocodile Crocodylus porosus 45 6.0
Reptiles Komodo Dragon Varanus komodoensis 44 6.1
Reptiles European leaf toed gecko Euleptes europaea 48 8.9
Reptiles Tiger rattlesnake Crotalus tigris 44 5.7
Amphibians Common frog Rana temporaria 44 6.1
Amphibians Common toad Bufo bufo 44 6.9
Amphibians Two-lined aecilian Rhinatrema bivittatum 75 6.0
Fish W. African Lungfish Protopterus annectens 44 5.6
Fish Thorny Skate Amblyraja radiata 44 5.6
Fish Sea Lamprey Petromyzon marinus 47 9.0

Secondary Structure

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The 5’ untranslated region is 56 base pairs long, and the 3’ untranslated region is 227 base pairs in length, spanning from base 1475 to 1702[16]. The 5’ UTR is predicted to have 1 stem loop, while the 3’ UTR can have as many as 4 stem loops, although its most stable structure has 2 stem loops[17].

Tertiary Structure

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Predicted structure of human WDR88 protein.

The WDR88 protein has 7 WD40 repeats each of which form an antiparallel blade, all together forming a beta propeller[18]. The presence of a 7-bladed beta propeller is generally conserved in orthologs from mammals to fish.

Transcript Level Regulation

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Transcription Factors

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Notable transcription factors include: Nr1h::Rxra, EBF1, and PLAG1. ZNFs (zinc finger proteins) and SOX (SRY-related HMG box) transcription factors are common.

Nr1h3::Rxra (Liver X receptor alpha, retinoid receptor X alpha) play a role in lipid metabolism, inflammation, and cholesterol homeostasis[19] . Dysregulation of these processes are implicated in prostate cancer progression. Decreased expression of this factor means pro-inflammatory gene expression can increase, leading to inflammation (a risk factor for prostate cancer). This factor can also interfere with androgen receptor pathways, which may influence androgen-dependent prostate cancer cell growth.

EBF1 (Early B-cell factor 1) may contribute to the development of schizophrenia through its role in neurodevelopment and immune system function[20] . Specifically, EBF1 can work with microRNAs to create regulatory loops to influence the onset and progression of schizophrenia.

PLAG1 (Pleomorphic adenoma gene 1) is associated with pleomorphic adenomas of the salivary gland. Chromosomal translocations of the target sequence can over-activate PLAG1, leading to an overactivation of downstream factors/targets that are involved in cell proliferation, leading to cancerous growths[21] . Cancer of the salivary gland can lead to dry mouth, which is a risk factor of Candidiasis (thrush) and other oral fungal infections.

microRNA

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microRNA (miRNA) binding sites are only found within the 3’ untranslated region[22]. Notably, the miRNA hsa-miR-191-5p is associated with various types of cancer due to its ability to act as an oncogene by promoting cell differentiation & migration[23].

Binding Proteins

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RNA binding protein binding regions are found within the 5’ and 3’ untranslated regions[24]. Notable examples within the 5' region include ELF4B (E74-like factor 4B) and RBMX proteins. RBMX specifically has the ability to repair DNA damage, and can suppress tumorigenicity/progression of bladder cancer[25]. ELF4B is important in cell growth and differentiation, and dysregulation in this interaction could lead to cancer[26].

The 3' UTR binding proteins include IGF2BP1 (Insulin-like Growth Factor 2 MRNA Binding Protein 1), PTBP1 (Polypyrimidine Tract Binding Protein 1), RBMX proteins, and KHSRP (KH-Type Splicing Regulatory Protein).

IGF2BP1 is known to regulate mRNA stability, splicing, and translation[27] . In the context of cancer, IGF2BP1 may impact tumor progression and metastasis by stabilizing oncogenic mRNAs and promoting cell proliferation.

PTBP1 (Polypyrimidine Tract Binding Protein 1) is known for its role in splicing regulation[28] . It may also influence the stability and translation of cancer-related transcripts, potentially contributing to cancer development.

KHSRP (KH-Type Splicing Regulatory Protein) is involved in the regulation of mRNA processing, including splicing and decay[29]. It has been implicated in the regulation of various cancer-related genes and may play a role in cancer progression.

Protein Level Regulation

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Post Translational Modifications

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Sites of likely post translational modifications. Phosphorylation sites were moderately to highly conserved among orthologs. Made with BioCuckoo Illustrator for Biological Sequences.[30] .

The WDR88 protein is predicted to be hyperphosphorylated, with an additional acetylation site and ubiquitination site[31][32][33]. The presence of multiple phosphorylation sites is conserved among orthologs. The WDR88 protein may also have N- and O-glycosylation sites[34][35].

 
Immunofluorescent staining of human WDR88, showing localization in nucleoplasm (green) and Golgi body (red). Image courtesy of ThermoFisher[36]

Subcellular Location

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The WDR88 protein is primarily located within the nucleus, with its location being conserved in orthologs[37].

Evolution

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Paralogs

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Corrected sequence divergence vs. median date of divergence of human WDR88, cytochrome c, fibrinogen alpha, and DAW1.

WDR88 paralogs include WDR5 (WD repeat containing protein 5), APAF1 (Apoptotic protease activating factor 1), WDR38, PAF1 (Protease activating factor 1), and DAW1 (dynein assembly factor with WD repeats 1)[38].

Orthologs

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Phylogenetic tree of WDR88 in20 vertebrate orthologs. Made with the assistance of phylogeny.fr.[39]

WDR88 in Homo sapiens is highly conserved. Its found in many vertebrate organisms, including other mammals, birds, reptiles, amphibians, and fish. It has not been identified in invertebrates[40]. Table 2 shows a selection of orthologs in mammals, birds, reptiles, amphibians, and fish. Many conserved regions fell within the WD repeat domain, and most WD dipeptides were conserved among close and distant orthologs.

Phylogeny & History

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The WDR88 gene is evolving relatively quickly compared to cytochrome c and DAW1, but slower than the rate of fibrinogen alpha.

Interacting Proteins

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Human WDR88 protein has notable interactions with the following proteins which are all associated with cell cycle regulation: KIA1429, FOS family proteins, NUDC, and WDR31. These interactions implicate human WDR88 in cell regulation processes[41].

WDR88 is also associated with argG (citrate-aspartate ligase), metE (cobalamin-independent methionine synthase), GATM (glycine amidinotransferase), and TYR (tyrosinase), which are in arginine, methionine, creatinine, and melanin synthesis (respectively)[42] .

WDR88 can also interact with proteins associated with the bacterium Yersinia pestis, which causes plague.

Clinical Significance

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In uterine & endometrial carcinoma, the WDR88 gene may serve as a relevant biomarker, and could also be a potential therapeutic target[43]. In prostate cancer, WDR88 can function as a marker for onset[44]

There is a significant association between a WDR88 gene variant and increased susceptibility to Candidiasis, an oral fungal infection[45]. A single nucleotide polymorphism at position 1328 changes from a cytosine to a thymine, causing an isoleucine to mutation to an alanine at position 424.

Exome array data showed 7 rare WDR88 variants contribute to the “genetic architecture of schizophrenia”[46]. 2 of these variants are predicted to be damaging or possibly damaging.

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    Part 1 of 3 of a conceptual translation of human WDR88 protein (isoform 1)
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    Part 2 of 3 of a conceptual translation of human WDR88 protein (isoform 1)
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    Part 3 of 3 of a conceptual translation of human WDR88 protein (isoform 1)
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    Variant Key for Conceptual Translation of Human WDR88
  1. ^ [Homo sapiens WD repeat domain 88 (WDR88), transcript variant 1, mRNA - Nucleotide - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/nuccore/NM_032319.3)
  2. ^ [GeneCards: WDR88 - Gene Details](https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR88)
  3. ^ [AceView: Gene:WDR88, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView. (nih.gov)](https://aceview.genomics.org/)
  4. ^ [Human hg38 chr19:33132114-33175799 UCSC Genome Browser v467](https://genome.ucsc.edu/)
  5. ^ [Homo sapiens WD repeat domain 88 (WDR88), transcript variant 1, mRNA - Nucleotide - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/nuccore/NM_032319.3)
  6. ^ [WDR88 WD repeat domain 88 [Homo sapiens (human)] - Gene - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/gene/27251)
  7. ^ [AceView: Gene:WDR88, a comprehensive annotation of human, mouse and worm genes with mRNAs or ESTsAceView. (nih.gov)](https://aceview.genomics.org/)
  8. ^ [WD repeat-containing protein 88 [Homo sapiens] - Protein - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/protein/NP_114571.1)
  9. ^ [GDS3113 / 224297 (nih.gov)](https://www.ncbi.nlm.nih.gov/gds/?term=GDS3113%20%2F%20224297)
  10. ^ Borodin, Y. I., Lomshakov, A. A., Astashov, V. V., Kazakov, O. V., Mayorov, A. P., & Larionov, P. M. (2014). Thymus in experimental carcinogenesis of the prostate gland. Bulletin of Experimental Biology and Medicine, 157, 724–727. https://doi.org/10.1007/s10517-014-2647-4
  11. ^ [GDS3113 / 224297 (nih.gov)](https://www.ncbi.nlm.nih.gov/gds/?term=GDS3113%20%2F%20224297)
  12. ^ [PSORT: Protein Subcellular Localization Prediction Tool (genscript.com)](https://www.genescript.com/psort.html)
  13. ^ [WD repeat-containing protein 88 [Homo sapiens] - Protein - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/protein/NP_114571.1)
  14. ^ [Expasy - Compute pI/Mw tool](https://web.expasy.org/compute_pi/)
  15. ^ [ebi.ac.uk/jdispatcher/seqstats/saps](https://www.ebi.ac.uk/Tools/seqstats/saps/)
  16. ^ [WD repeat-containing protein 88 [Homo sapiens] - Protein - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/protein/NP_114571.1)
  17. ^ [RNA Folding Form (unafold.org)](https://unafold.rna.albany.edu/?q=RNA-Folding-Form)
  18. ^ [WD repeat-containing protein 88 [Homo sapiens] - Protein - NCBI (nih.gov)](https://www.ncbi.nlm.nih.gov/protein/NP_114571.1)
  19. ^ Silva, K.C.S.; Tambwe, N.; Mahfouz, D.H.; Wium, M.; Cacciatore, S.; Paccez, J.D.; Zerbini, L.F. (2024). "Transcription Factors in Prostate Cancer: Insights for Disease Development and Diagnostic and Therapeutic Approaches". Genes, 15, 450. [1](https://doi.org/10.3390/genes15040450)
  20. ^ Guo, AY.; Sun, J.; Jia, P.; et al. (2010). "A Novel microRNA and transcription factor mediated regulatory network in schizophrenia". BMC Systems Biology, 4, 10. [2](https://doi.org/10.1186/1752-0509-4-10)
  21. ^ Wang, Y.; Shang, W.; Lei, X.; et al. (2013). "Opposing functions of PLAG1 in pleomorphic adenoma: a microarray analysis of PLAG1 transgenic mice". Biotechnology Letters, 35, 1377–1385. [3](https://doi.org/10.1007/s10529-013-1213-7)
  22. ^ [miRDB - Custom Prediction](http://mirdb.org/miRDB/)
  23. ^ Persson, H., Kvist, A., Rego, N., Staaf, J., Vallon-Christensson, J., Lutts, L., Loman, N., Jonsson, G., Naya, H., Hoglund, M., Borg, A., Rovira, C. (2011). Identification of New MicroRNAs in Paired Normal and Tumor Breast Tissue Suggests a Dual Role for the ERBB2/Her2 Gene. Molecular and Cellular Pathobiology, 71(1), 71-86. https://doi.org/10.1158/0008-5472.CAN-10-1869
  24. ^ [RBPDB: The database of RNA-binding specificities (utoronto.ca)](https://rbpdb.ccbr.utoronto.ca/)
  25. ^ The role of mitochondria in cancer therapy: a review. Nature Reviews Cancer (2021). [4](https://doi.org/10.1038/s41388-021-01666-z)
  26. ^ Sonenberg, Nahum; Gingras, Anne-Claude (1998). "The mRNA 5′ cap-binding protein eIF4E and control of cell growth". Current Opinion in Cell Biology, 10 (2), 268–275.
  27. ^ Glaß, Markus; Misiak, Danny; Bley, Nadine; Müller, Simon; Hagemann, Sven; Busch, Bianca; Rausch, Alexander; Hüttelmaier, Stefan (2021). "IGF2BP1, a Conserved Regulator of RNA Turnover in Cancer". Frontiers in Molecular Biosciences, Volume 8, Section RNA Networks and Biology. [5](https://doi.org/10.3389/fmolb.2021.632219)
  28. ^ Guo, Jihua; Jia, Jun; Jia, Rong (2015). "PTBP1 and PTBP2 impaired autoregulation of SRSF3 in cancer cells". Scientific Reports, 5, Article 14548. [6](https://doi.org/10.1038/srep14548)
  29. ^ Adamson, Britt; Smogorzewska, Agata; Sigoillot, Frederic D.; King, Randall W.; Elledge, Stephen J. (2012). "A genome-wide homologous recombination screen identifies the RNA-binding protein RBMX as a component of the DNA-damage response". Nature Cell Biology, 14, pp. 318–328.
  30. ^ "BioCuckoo". [7](http://ibs.biocuckoo.org/online.php). Accessed on 27 July 2024.
  31. ^ [ELM - unknown](https://elm.eu.org/)
  32. ^ [ELM - search the eukaryotic linear motif resource](https://elm.eu.org/)
  33. ^ [Motif Scan (sib.swiss)](https://www.expasy.org/tools/motif_scan)
  34. ^ [NetNGlyc 1.0 - DTU Health Tech - Bioinformatic Services](https://www.cbs.dtu.dk/services/NetNGlyc/)
  35. ^ [DictyOGlyc 1.1 - DTU Health Tech - Bioinformatic Services](https://www.cbs.dtu.dk/services/DictyOGlyc/)
  36. ^ [WDR88 Polyclonal Antibody (PA5-98512) (thermofisher.com)](https://www.thermofisher.com/order/catalog/product/PA5-98512)
  37. ^ [PSORT: Protein Subcellular Localization Prediction Tool (genscript.com)](https://www.genescript.com/psort.html)
  38. ^ [Protein BLAST: search protein databases using a protein query (nih.gov)](https://blast.ncbi.nlm.nih.gov/Blast.cgi)
  39. ^ "Phylogeny.fr Simple Phylogeny". phylogeny.fr. Retrieved 2024-07-27.
  40. ^ [Protein BLAST: search protein databases using a protein query (nih.gov)](https://blast.ncbi.nlm.nih.gov/Blast.cgi)
  41. ^ [PSICQUIC View (ebi.ac.uk)](https://www.ebi.ac.uk/psicquic)
  42. ^ "IntAct - Search Results". ebi.ac.uk. Retrieved 2024-07-27.
  43. ^ Chetverina, D., Vorobyeva, N. E., Gyorffy, B., Shtil, A. A., & Erokhin, M. (2023). Analyses of genes critical to tumor survival reveal potential ‘supertargets’: Focus on transcription. Cancers, 15(11), 3042. https://doi.org/10.3390/cancers15113042
  44. ^ Jaiswal, R., Jauhari, S., & Rizvi, S. A. M. (n.d.). WDR88, CCDC11, and ARPP21 genes indulge profoundly in the desmoplastic retort to prostate and breast cancer metastasis. bioRxiv. https://doi.org/10.1101/178566
  45. ^ Jiang, L., Kerchberger, V. E., Shaffer, C. et al. (2022). Genome-wide association analyses of common infections in a large practice-based biobank. BMC Genomics, 23, 672. https://doi.org/10.1186/s12864-022-08888-9
  46. ^ Richards AL, Leonenko G, Walters JT, Kavanagh DH, Rees EG, Evans A, Chambert KD, Moran JL, Goldstein J, Neale BM, McCarroll SA, Pocklington AJ, Holmans PA, Owen MJ, O'Donovan MC. (2016). Exome arrays capture polygenic rare variant contributions to schizophrenia. Hum Mol Genet. 25(5):1001-7. doi: 10.1093/hmg/ddv620. Epub 2016 Jan 5. PMID: 26740555; PMCID: PMC4754044

References

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