WDR88 (WD repeat containing protein 88) is a protein, which in humans, is encoded by the gene WDR88.[5] It consists of seven WD40 repeats, which form a seven-bladed beta-propeller. Mutations within the WDR88 gene are associated with a variety of cancers, as well as schizophrenia and fungal infections.
The protein structure of WDR88 is characterized by the presence of seven WD40 repeats, which are short structural motifs of approximately 40 amino acids that often terminate in a tryptophan-aspartic acid (WD) dipeptide. These repeats typically form a beta-propeller structure, suggesting a potential role in protein-protein interactions.[6]
Gene
WDR88 gene on human chromosome 19. Image courtesy of GeneCards.[7]
The WDR88 gene is on chromosome 19 at position 19q13.11 on the plus strand.[8] The gene is encoded from position 33,132,114 to 33,175,799.[9] 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).[10] The WDR88 gene may also be referred to as PQWD (PQQ repeat containing and WD repeat containing gene).[citation needed]
Transcripts
The gene WDR88 has 3 isoforms.[8] The splice variants of the WDR88 transcript vary according to their first and last exon and their last two introns. This isoform (aAug10) has an mRNA sequence of 1702 nucleotides.[citation needed]
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
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.[6][11] 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).[12]
Other tissues with moderate expression include the heart, skeletal muscle, brain, kidney, lymph nodes, and ovaries.[11]
Protein
The WDR88 protein is a nuclear protein.[13] 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.[11][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.[citation needed]
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
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.[6] 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.[16]
Tertiary Structure
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.[6] The presence of a 7-bladed beta propeller is generally conserved in orthologs from mammals to fish.[citation needed]
Transcript Level Regulation
Transcription Factors
Notable transcription factors include: Nr1h::Rxra, EBF1, and PLAG1. ZNFs (zinc finger proteins) and SOX (SRY-related HMG box) transcription factors are common.[17]
Nr1h3::Rxra (Liver X receptor alpha, retinoid receptor X alpha) play a role in lipid metabolism, inflammation, and cholesterol homeostasis.[18] 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.[citation needed]
EBF1 (Early B-cell factor 1) may contribute to the development of schizophrenia through its role in neurodevelopment and immune system function.[19] Specifically, EBF1 can work with microRNAs to create regulatory loops to influence the onset and progression of schizophrenia.[citation needed]
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.[20] Cancer of the salivary gland can lead to dry mouth, which is a risk factor of Candidiasis (thrush) and other oral fungal infections.[citation needed]
microRNA
microRNA (miRNA) binding sites are only found within the 3' untranslated region.[21] 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[22]
Binding Proteins
RNA binding protein binding regions are found within the 5' and 3' untranslated regions.[23] 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.[24] ELF4B is important in cell growth and differentiation, and dysregulation in this interaction could lead to cancer<.[25]
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). [citation needed]
IGF2BP1 is known to regulate mRNA stability, splicing, and translation.[26] In the context of cancer, IGF2BP1 may impact tumor progression and metastasis by stabilizing oncogenic mRNAs and promoting cell proliferation.[citation needed]
PTBP1 (Polypyrimidine Tract Binding Protein 1) is known for its role in splicing regulation.[27] It may also influence the stability and translation of cancer-related transcripts, potentially contributing to cancer development.[citation needed]
KHSRP (KH-Type Splicing Regulatory Protein) is involved in the regulation of mRNA processing, including splicing and decay.[28] It has been implicated in the regulation of various cancer-related genes and may play a role in cancer progression.[citation needed]
Protein Level Regulation
Post Translational Modifications
Sites of likely post translational modifications. Phosphorylation sites were moderately to highly conserved among orthologs. Made with BioCuckoo Illustrator for Biological Sequences.[29]
Immunofluorescent staining of human WDR88, showing localization in nucleoplasm (green) and Golgi body (red). Image courtesy of ThermoFisher<.[35]
Subcellular Location
The WDR88 protein is primarily located within the nucleus, with its location being conserved in orthologs.[13]
Evolution
Paralogs
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).[36]
Orthologs
Phylogenetic tree of WDR88 in20 vertebrate orthologs. Made with the assistance of phylogeny.fr.[37]
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.[36] 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.
WDR88 Protein Alignment Gallery
Multiple Sequence Alignment[38] of WDR88 protein among humans and 20 orthologs. Exon boundaries are shown in black, WD domains in orange brackets, and WD40 repeats in gray highlighting. [citation needed]
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.[39][40][41][42][43][44]
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).[39]
In uterine & endometrial carcinoma, the WDR88 gene may serve as a relevant biomarker, and could also be a potential therapeutic target.[45] In prostate cancer, WDR88 can function as a marker for onset[46]
Exome array data showed 7 rare WDR88 variants contribute to the "genetic architecture of schizophrenia".[48] 2 of these variants are predicted to be damaging or possibly damaging.
^Wang Y, Shang W, Lei X, Shen S, Zhang H, Wang Z, et al. (September 2013). "Opposing functions of PLAG1 in pleomorphic adenoma: a microarray analysis of PLAG1 transgenic mice". Biotechnology Letters. 35 (9): 1377–1385. doi:10.1007/s10529-013-1213-7. PMID23690029.
^Persson H, Kvist A, Rego N, Staaf J, Vallon-Christersson J, Luts L, et al. (January 2011). "Identification of new microRNAs in paired normal and tumor breast tissue suggests a dual role for the ERBB2/Her2 gene". Cancer Research. 71 (1): 78–86. doi:10.1158/0008-5472.CAN-10-1869. PMID21199797.
^Sonenberg N, Gingras AC (April 1998). "The mRNA 5' cap-binding protein eIF4E and control of cell growth". Current Opinion in Cell Biology. 10 (2): 268–275. doi:10.1016/s0955-0674(98)80150-6. PMID9561852.
^Jaiswal R, Jauhari S, Rizvi SA (2017). "WDR88, CCDC11, and ARPP21 genes indulge profoundly in the desmoplastic retort to prostate and breast cancer metastasis". bioRxiv10.1101/178566.
