WDR88 (WD repeat containing protein 88) is a protein, which in humans, is encoded by the gene WDR88.[1] 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.
The WDR88 gene is on chromosome 19 at position 19q13.11 on the plus strand.[2] The gene is encoded from position 33,132,114 to 33,175,799.[3] It has 11 exons, and is approximately 1702 base pairs long. 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).[4] The WDR88 gene may also be referred to as PQWD (PQQ repeat containing and WD repeat containing gene).
The gene WDR88 has 3 isoforms. 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.
| 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 |
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.[5] [6] 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).[7] Other tissues with moderate expression include the heart, skeletal muscle, brain, kidney, lymph nodes, and ovaries.
The WDR88 protein is a nuclear protein.[8] 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.[9] In addition, there is an increased abundance of cysteine, aspartic acid, and serine residues.[10] 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.
| 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 |
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. 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.[11]
The WDR88 protein has 7 WD40 repeats each of which form an antiparallel blade, all together forming a beta propeller. The presence of a 7-bladed beta propeller is generally conserved in orthologs from mammals to fish.
Notable transcription factors include: Nr1h::Rxra, EBF1, and PLAG1. ZNFs (zinc finger proteins) and SOX (SRY-related HMG box) transcription factors are common.[12]
Nr1h3::Rxra (Liver X receptor alpha, retinoid receptor X alpha) play a role in lipid metabolism, inflammation, and cholesterol homeostasis.[13] 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.[14] 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.[15] Cancer of the salivary gland can lead to dry mouth, which is a risk factor of Candidiasis (thrush) and other oral fungal infections.
microRNA (miRNA) binding sites are only found within the 3' untranslated region.[16] 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[17]
RNA binding protein binding regions are found within the 5' and 3' untranslated regions.[18] 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.[19] ELF4B is important in cell growth and differentiation, and dysregulation in this interaction could lead to cancer<.[20]
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.[21] 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.[22] 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.[23] It has been implicated in the regulation of various cancer-related genes and may play a role in cancer progression.
The WDR88 protein is predicted to be hyperphosphorylated, with an additional acetylation site and ubiquitination site.[24] [25] [26] The presence of multiple phosphorylation sites is conserved among orthologs. The WDR88 protein may also have N- and O-glycosylation sites<[27] [28] .
The WDR88 protein is primarily located within the nucleus, with its location being conserved in orthologs.
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).[29]
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. 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.
Multiple Sequence Alignment[30] 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.
The WDR88 gene is evolving relatively quickly compared to cytochrome c and DAW1, but slower than the rate of fibrinogen alpha.
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.[31] [32] [33] [34] [35] [36]
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).
WDR88 can also interact with proteins associated with the bacterium Yersinia pestis, which causes plague.
In uterine & endometrial carcinoma, the WDR88 gene may serve as a relevant biomarker, and could also be a potential therapeutic target.[37] In prostate cancer, WDR88 can function as a marker for onset[38]
There is a significant association between a WDR88 gene variant and increased susceptibility to Candidiasis, an oral fungal infection.[39] 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".[40] 2 of these variants are predicted to be damaging or possibly damaging.
| 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 |
Conceptual translation of human WDR88 protein, isoform 1, with key of variants.[42]