WDR88 (WD repeat containing protein 88) is a protein, which in humans, is encoded by the gene WDR88. 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.
Gene
The WDR88 gene is on chromosome 19 at position 19q13.11 on the plus strand. The gene is encoded from position 33,132,114 to 33,175,799. 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). The WDR88 gene may also be referred to as PQWD (PQQ repeat containing and WD repeat containing gene).
Transcripts 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.
Tissue Expression 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. 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). Other tissues with moderate expression include the heart, skeletal muscle, brain, kidney, lymph nodes, and ovaries.
Protein The WDR88 protein is a nuclear protein. 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. In addition, there is an increased abundance of cysteine, aspartic acid, and serine residues. 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.
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. 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.
Tertiary Structure
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.
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. Nr1h3::Rxra (Liver X receptor alpha, retinoid receptor X alpha) play a role in lipid metabolism, inflammation, and cholesterol homeostasis. 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. 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. Cancer of the salivary gland can lead to dry mouth, which is a risk factor of Candidiasis (thrush) and other oral fungal infections.
microRNA microRNA (miRNA) binding sites are only found within the 3' untranslated region. 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
Binding Proteins RNA binding protein binding regions are found within the 5' and 3' untranslated regions. 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. ELF4B is important in cell growth and differentiation, and dysregulation in this interaction could lead to cancer<. 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. 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. 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. It has been implicated in the regulation of various cancer-related genes and may play a role in cancer progression.
Protein Level Regulation
Post Translational Modifications
The WDR88 protein is predicted to be hyperphosphorylated, with an additional acetylation site and ubiquitination site. The presence of multiple phosphorylation sites is conserved among orthologs. The WDR88 protein may also have N- and O-glycosylation sites
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Subcellular Location The WDR88 protein is primarily located within the nucleus, with its location being conserved in orthologs.
Evolution
Paralogs
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![WDR88: WDR88 gene on human chromosome 19[7]](https://upload.wikimedia.org/wikipedia/commons/thumb/1/1a/WDR88C19.png/500px-WDR88C19.png?utm_source=en.wikipedia.org&utm_campaign=parser&utm_content=thumbnail)
