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Wd repeat domain 76

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Last Updated: 02 July 2021

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Wd repeat domain 76

Identifiers
AliasesWDR76 , CDW14, WD repeat domain 76
External IDsMGI: 1926186 HomoloGene: 38573 GeneCards: WDR76
Orthologs
Wikidata
View/Edit HumanView/Edit Mouse

Numerous cell signaling pathways are regulated by the ubiquitin-proteasome system. Ubiquitination of target protein generally requires joint action of three enzymes. First, E1 activates ubiquitin molecule; E2 then bind ubiquitin molecule; and finally, E3 ubiquitin ligase binds to a specific substrate and E2 covalently transfers ubiquitin protein to one or more lysine residues of the target protein. Thousands of ubiquitination processes are ongoing in cell at any moment. The high specificity of this degradation mechanism targeting specific proteins is determined mainly by E3 ubiquitin ligase. Therefore, E3 ligase plays a key role in degradation of target protein. E3 ubiquitin ligases with RING domain comprise large group of E3 ubiquitin ligases that is responsible for ~20% of ubiquitin-mediate protein degradation; additionally, degradation events regulated by Cullin RING ligases, which are composed of Cullin proteins, account for a large proportion. Previous studies have shown that CRLs not only are primary factors in protein degradation but also are involved in initiation and progression of some cancers, including colorectal cancer, cholangiocarcinoma, etc. The Cul protein family was first reported in 1996 to form an active complex that can regulate cell cycle. The human genome contains 7 Cul proteins, including, Cul1, Cul2, Cul3, Cul4A, Cul4B, Cul5, Cul7 and Cul9. All six have conserve, homologous cul domains, which function to bind subunit RING domain proteins RING-box protein 1 1 or Rbx 2 in the whole complex. In addition to Cul7 and Cul9, five other members have three serial N-terminal Cul repeats, which are used to recognize subunits in the E3 ubiquitin ligase complex. Since it was discovered and defined nearly 20 years ago, subsequent studies have revealed that the multipart E3 ligase complex consisting of this family of proteins has intricate structure and serves important functions in cell cycle, signal transduction, cell development and other physiological processes. Among CRLs, CRL1 has been extensively study. The SCF complex is composed of Cul1, Rbx1, linker protein Skp1 and variable F-box proteins. Within the SCF structure, differences in FBX proteins, determine specificity of substrate binding to accomplish degradation of different substrates. To date, 69 FBX proteins have been found and identified in the human genome, and most can form the CRL1 complex. FBX proteins can be roughly divided into three types according to other domains present: i FBXW, which contains tryptophan-aspartic acid 40 WD40 repeat domain; ii FBXL, which contains leucine-rich repeat domain; and iii FBXO, which contains other domain motifs. Accumulating evidence has indicated that dysregulation of FBX proteins is involved in development, angiogenesis, proliferation and metastasis of the number of malignancies 9. F-box / WD repeat-containing protein 7 FBXW7 is also called AGO, hCDC4 and SEL-10; SEL-10 was first identified from yeast, AGO was first found in Drosophila, and CDC4 is yeast gene 15.

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Translational regulation

Blades of WDR domain each contain conserve glycine-histidine and tryptophan-aspartate motif. Structural adaptability allows WDRs to retain their-propeller fold upon deletion or insertion of WD repeats, number of which can vary from five to eight 13 14. WDR domains typically act as scaffolds, often within large multiprotein complexes 15. The top, bottom, and side surfaces of the donut can simultaneously act as interaction sites for diverse binding partners, including proteins, peptides, RNA and DNA, suggesting that multiple surfaces can potentially be targeted by chemical inhibitors. For instance, EZH2, SUZ12, and activating histone peptide all exploit distinct surfaces of EED within the PRC2 complex, while WDR domain of DDB2 binds damage DNA. WDRs can also specifically recognize post-translational modifications on proteins: EED binds tri-methylated lysines 16, WDR5 binds methylated arginines 17, while yeast Cdc4 and Human FBXW7 bind phosphothreonine / phosphoserine degron motifs via their central cavity 18 19. Probably due to their versatility as protein interaction scaffolds, WDRs are the fourth most abundant domain in Human proteome 15. Systematic search identifies 361 WDR-containing proteins in Human, but this number is probably a conservative estimate, as WDR sequences are poorly conserved outside of their defined WD di-peptide motifs, and are poorly annotate in public databases. An algorithm that is comparatively sensitive to WD repeats was recently developed to annotate WDR proteins 20 21. The number of-propeller domains is even larger when structurally related Kelch domains and other domains are taken into consideration 22. Additionally, in yeast, where interactome is best characterized, WDR domains engage in more protein-protein interactions than any other domain 15, emphasizing the ubiquitous role of these domains in connecting global protein interaction network. As a consequence of their prevalence in human proteome, WDR domains are involved in a wide spectrum of cellular networks, many of which are perturb in human diseases. Cellular pathways from Reactome database 23 were ranked based on the number of WDR proteins involve. At the top of the list, at least 49 WDR proteins are known to participate in regulation of gene expression. Among these, 15 are components of Chromatin complexes, including EED and WDR5, for which potent inhibitors have been reported 24-26. WDRs are also found in pathways that are targeted by existing drugs, such as DNA repair or immune system, in emerging areas of drug discovery, such as Chromatin mediate signaling or splicing, and in cellular networks that have so far proven largely undruggable, such as extensive ubiquitin-proteasome systems that exert post-translational control over most of proteome. In some cases, disease association is direct and causative. For instance, recognition of Cyclin E phosphothreonine degron motif by the central pocket of WDR domain of FBXW7 leads to Cyclin E degradation, which restrains DNA replication and thereby helps ensure genome stability.

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Epigenetic regulation

Table

Methylated SequenceCleaved byNot Cleaved by
m4 CCGGMspI (C/CGG)HpaII (C/CGG)
C m5 CGGMspI (C/CGG)HpaII (C/CGG)
C m4 CGGMspI (C/CGG)HpaII (C/CGG)
CC m5 CGGGXmaI (C/CCGGG)SmaI (CCC/GGG)
G m6 ATCSau3AI (/GATC)MboI, NdeII (/GATC)
GAT m5 CMboI, NdeII (/GATC)Sau3AI (/GATC)
GAT m4 CMboI (/GATC)Sau3AI (/GATC)
GGTAC m5 CKpnI (GGTAC/C)Acc65I (G/GTACC)

Ferroptosis, novel mode of nonapoptotic Cell death, involves metabolic dysfunction that results in production of irondependent reactive Oxygen species, iron carrier Protein, intracellular metabolic process, and related regulators. Previous studies have linked ferroptosis with oncogenic Ras, and the P53 tumor suppressor positively regulates ferroptosis by transcriptionally inhibiting expression of cysteine / glutamate antiporter, which is encoded by SLC7A11 gene in Human. Whether other factors such as epigenetic factors are involved in the process remains less know. Chromatin modifier lymphoid specific helicase contributes to malignant progression of nasopharyngeal carcinoma and glioma. We recently indicated that LSH was shown to cooperate with partners, such as G9a, to drive cancer progression. However, molecular mechanisms, particularly in lung cancer, are not well understood. Importantly, impact of ferroptosis on cancer progression, especially in Chromatin remodeling, is still far from fully understand. Base on the study report in the article entitled EGLN1 / cMyc induce lymphoidspecific helicase inhibits ferroptosis through lipid metabolic gene expression changes, which was recently published in Theranostics by Jiang et al., Such interplay between epigenetic controls in Chromatin remodeling and ferroptosis has been address. Using RNA sequencing and gene ontology analysis, we first identified significant enrichment in pathways that relate to the metabolic process and Warburg effect. Moreover, link between LSH and metabolic genes prompts US to assess expression of two groups of metabolic genes. The first group comprised glucose transporters, which were important in glucose transport, and the other group comprised fatty acid desaturases, which were dependent on reduced nicotinamide adenine dinucleotide Phosphate. We demonstrate that LSH contributes to lung cancer progression by directly upregulating metabolic genes including stearoylCoA desaturase 1 and FADS2. LSHmediated increases in metabolic gene expression may occur through DNA methylationindependent mechanism rather than through Chromatin Regulation. Furthermore, our findings provide evidence for interaction between LSH and WD Repeat Domain 76, which is a nuclear Protein containing tandem copies of WD Repeats that has unknown function in mammals. LSHdependent recruitment of WDR76 to metabolic gene promoters and subsequent Chromatin modification that leads to metabolic gene activation links epigenetic Regulation by LSH to upregulation of emerging metabolic genes. The ferroptotic mode of programmed necrosis was recently discovered as apoptosisindependent form of cell death in Rastransformed cells; K Ras mutant is common in lung cancer. Ferroptotic death is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy. This process is characterized by overwhelming, irondependent accumulation of lethal lipid ROS. We next demonstrate that LSH decreases lipid ROS and iron concentrations, which support the inhibitory role of LSH in ferroptosis. We demonstrate that LSH is resistant to ferroptotic cell death in cancer cells after treatment of erastin, ferroptosis inducer, and inhibits ferroptosis by inhibiting the cysteine / glutamate antiporter System. RNA sequencing analysis results also show that LSH is significantly associated with metabolic process, indicating that LSH inhibits ferroptosis by affecting these metabolic genes.


DNA Methylation

Many important regulatory proteins contain domains that bind to modified residues, including plant homeobox domain fingers, bromodomains, chromatin organization modifier domains, WD40 repeat and tudor domains. Transcription-friendly H3K4me3 acts as a binding site for effector proteins that contain PHD finger, such as nucleosome remodeling factor and ING4-containing histone acetyltransferase complex. H3K36me2 modification, which interferes with transcription initiation, acts as a binding site for chromodomain of RPD3S histone deacetylase complex. Histone modifications also act in cooperation. Specific combinations of histone modifications at a particular site often determine which protein complexes and accessory proteins are recruited to activate or repress transcription directly, catalyze additional histone modifications or recruit other histone-modifying proteins. This cooperativity can be explain, at least in part, by the fact that these proteins can contain one or more modified-histone-binding domains. For example, TFIID protein complex contains both PHD finger and bromodomain and so bind more strongly to H3K4me3 marks near acetylate H3K9 and H3K14 residues. Absence of one of these domains through gene mutation or rearrangement can cause serious lapses in gene regulation and diseases such as cancer. Recently, researchers characterized translocation involving histone demethylase KDM5A that results in fusion of H3K4me3-binding PHD finger of KDM5A to transcriptional activator NUP98, common leukemia translocation partner, in acute myeloid leukemia patient. Similarly, mixed lineage leukemia family members, which act as histone methyltransferases, are involved in translocations in MLL.

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Autoubiquitination

Table

Methylated SequenceCleaved byNot Cleaved by
m4 CCGGMspI (C/CGG)HpaII (C/CGG)
C m5 CGGMspI (C/CGG)HpaII (C/CGG)
C m4 CGGMspI (C/CGG)HpaII (C/CGG)
CC m5 CGGGXmaI (C/CCGGG)SmaI (CCC/GGG)
G m6 ATCSau3AI (/GATC)MboI, NdeII (/GATC)
GAT m5 CMboI, NdeII (/GATC)Sau3AI (/GATC)
GAT m4 CMboI (/GATC)Sau3AI (/GATC)
GGTAC m5 CKpnI (GGTAC/C)Acc65I (G/GTACC)

Genetic Mutations impair FBXW7-mediate Oncogene degradation. FBXW7 recognizes its substrate through conserving CDC4 phosphodegron motif, which requires substrate to be phosphorylated by Kinase. SCF Complex, which consists of SKP1, CUL1, RBX1 and FBXW7, interacts with substrate through FBXW7 and adds Ubiquitin to substrates. Poly-ubiquitinated substrates are then targeted by Proteasome for degradation. FBXW7-substrate interaction can be de-stabilize through: Mutations in substrate that prevent interaction with FBXW7, Mutations in the WD40 domain of FBXW7 that impair its ability to interact with substrate, and Mutations in FBXW7 F-box domain that inhibit its ability to interact with substrate. These mutations have been reported in human cancers and may impair formation of SCF Complex and stabilize FBXW7 substrates co-occurrence of FBXW7 Mutations with 50 most frequently mutated genes. The 50 most frequently mutated genes are identified from the COSMIC database. Co-occurrence of FBXW7 mutation and 50 most frequently mutated genes are downloaded from cBioPortal database. The top panel shows cancer tissue types and names of cancer cell lines with FBXW7 Mutations. Red boxes indicate genetic mutations and green boxes represent wild-type genes

* Please keep in mind that all text is machine-generated, we do not bear any responsibility, and you should always get advice from professionals before taking any actions.

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Cyclin E

Coordinate progression through cell cycle is critical for eukaryotic cells 105. Eukaryotic cell cycle progression is mainly controlled by a family of protein kinases know as Cyclin-dependent kinases, which consist of activating Cyclin subunit and catalytic subunit CDK 39 106. CDK activities are controlled by availability of their Cyclin partners and expression of specific CDK inhibitors 103. Interestingly, WD40 proteins have emerged as crucial regulators of cell cycle progression via interacting with other proteins. Cell cycle progression is tightly controlled by UPS, as Cyclin expression levels are executed via UPS and CDKIs are targeted for degradation by UPS-mediate ubiquitination 107. Two Ubiquitin ligases, namely, SKP1-CUL1-Fbox-Protein Complex and Anaphase-Promoting Complex / Cyclosome, specifically function in ubiquitination of many of these CDKs and CDKIs 107. SCF can control transition of G1 / S, and two key targets of SCF, Cyclin E and CDKI p27 Kip1, are controlled by CUL4-DDB1 49 108. In addition, several F-box proteins with WD40 repeats, such as FBXW1, FBXW5, FBXW7 and FBXW8, can bind DDB1 through WD40 repeats in vitro in respond to DNA damage, Repair and Cell cycle progression 22. FBXW1 plays an important role in regulating cell cycle checkpoints 109. In response to genotoxic stress, it contributes to turning off CDK1 activity by mediating degradation of CDC25A in collaboration with CHK1 109 110, thereby preventing cell cycle progression before completion of DNA Repair 109 110. FBXW5 is a cell cycle-regulate Protein with expression levels peaking at G1 / S transition 111. FBXW5 levels are controlled by the Anaphase-Promoting Complex, which targets FBXW5 for degradation during mitosis and G1, thereby helping to reset centrosome duplication machinery 111. FBXW7 Protein is a well-establish Tumor suppressor and responsible for substrate recognition in SCF Ubiquitin ligase Complex 24 28. WD40 repeats in FBXW7 is essential for binding substrates such as Cyclin E, MYC, JUN and Notch 24. FBXW8 plays an essential role in Cancer cell proliferation through proteolysis of Cyclin D1, but it remains unclear whether FBXW8 is necessary for cell cycle progression in normal cells 25. CRL4A L2DTL E3 ligase also interacts with and targets Tumor suppressor Protein p53, mediating cell cycle arrest or apoptosis in response to genotoxic stress 112. CDC20 is WD40 Protein, which is an essential Cell-cycle regulator required for completion of mitosis in organisms from yeast to mammals 26. In mitosis, CDC20 binds to and activates Ubiquitin ligase activity of APC / C and enables ubiquitination and degradation of securin and Cyclin B 20. APC / C CDC20 contributes to proteolysis of securin, triggering chromosomal separation at Anaphase 107. The structure of the WD40 domain in CDC20 indicates that it folds into seven-bladed-propeller and has ideal architecture for multiple Protein-Protein interactions 113. Thus, CDC20 appears to bridge interactions between APC / C and its substrates through WD40 repeats 113. In budding yeast Saccharomyces cerevisiae, Sic1 encodes Cyclin-dependent Kinase inhibitor that regulates cell cycle at G1 to S transition by inhibiting activity of CDC28 114.

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Aurora A

Malformations of cerebral cortical development are outcome of disruptions in precisely orchestrated series of events that occur during embryonic and early postnatal life and define specification of neuronal identity and, ultimately, execution of neuronal differentiation and connectivity both within and outside the cerebral cortex. MCDs are neurodevelopmental disorders invariably causing developmental delay and were initially classified according to the phase at which disruptions of normal developmental events were thought to occur, impacting for example neural progenitor proliferation or apoptosis, neuronal migration, or cortical organization 1 2. Progress in our fundamental understanding of normal cortical development 3 4 5 along with advances in genetics, genomics, and imaging prompted revision of traditional classification 6. Importantly, early genetic studies lead to the realization that a subset of MCD disorders are indeed monogenic, potentially offering unique insights into specific cellular functions involved in brain pathobiology. The wide spectrum of MCD is underlain by genetic lesions, 6 17 of which are associated with autosomal recessive primary microcephaly, genetically heterogeneous disorder characterized by clinical finding of head circumference more than 2 standard deviations below ethnically-match age-and sex-related mean and thought to be secondary to abnormal neural progenitor proliferation or apoptosis 6 12 13 14. MCPH2, second most common form of primary microcephaly, is caused by recessive mutations in WDR62 15 16 17, gene encoding WD repeat-containing protein. Members of this large pan-eukaryotic protein family are thought to serve as rigid scaffolds coordinating multiprotein complex assemblies with diverse functions, including signal transduction, transcriptional regulation, cilia assembly, cell cycle control and apoptosis 18 19 20 21. When mutations in WDR62 were initially discovered 15, it became apparent that they cause form of microcephaly invariably accompanied by a wide spectrum of additional and diverse cortical abnormalities, including pachygyria, thicken cortex, lissencephaly, and polymicrogyria, which were traditionally thought to be distinct, suggesting they can have unify underlying genetic causation. More than 30 missense, nonsense, frameshift or splice site mutations mapping throughout genes have been reported in patients around world. Like many other MCPH-associated proteins, WDR62 has been implicated in spindle maintenance, mitotic progression and maintenance of neural progenitor pool 33 34 35 and has further shown to be associate with C-Jun N-terminal kinase and Aurora kinase 33 34 36 37 38 39. However, mechanisms by which WDR62 dysfunction results in such a diverse spectrum of structural brain abnormalities remain poorly understood. We investigate WDR62 function using mouse model and dermal fibroblasts from affected and unaffected members of family carrying novel truncating mutation in WDR62. Our studies demonstrate that disruption of WDR62 impairs proliferation of neocortical progenitors during late neurogenesis underlain by abnormalities in asymmetric centrosome inheritance causing microcephaly in mice, and impairs mitotic cycle progression in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase.

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Notch

Notch is a highly conserved signaling system in multicellular organisms, playing an important role in cell proliferation, differentiation and apoptosis. In mammals there are four isoforms of Notch receptors, all of which are single-pass transmembrane receptors in which the N-terminus is located outside the cell and accounts for most of the structure and only a small part is inside the cell. When ligand bind to the extracellular domain of Notch receptor, it can induce proteolysis reaction and release intracellular domain. The intracellular domain of Notch receptor acts as a transcription factor to regulate expression of specific genes. Overactivation of the Notch signaling pathway can cause abnormal cell proliferation and cancer. Ubiquitination of intracellular domain of Notch 1 and Notch 4 by FBXW7 significantly weakens Notch signal transduction, whereas inhibition of FBXW7 enhances Notch-mediate activation of downstream signaling. FBXW7 gene knockout results in abolishment of Notch 4 signal transmission, which can lead to abnormal development of blood vessels in mouse embryos and may result in death at ~11 days. Similarly, mice with brain-specific FBXW7 knockout succumb after birth owing to accumulation of Notch 1 and Notch 3 proteins in the brain, which results in increased expression of target genes and abnormal differentiation of neural stem cells, causing abnormal brain development and morphology in these mice.

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MCL-1

Recently, work performed in our laboratory demonstrated that Myeloid Cell leukemia-1 antagonism suppresses tumour progression in pre-clinical models of breast Cancer and revealed that, in addition to its role in cell survival, MCL-1 modulates cellular invasion. 1 MCL-1 was first described as an immediate-early response gene in human Myeloid leukaemia cells induced to differentiate with phorbol ester. 2 MCL-1 is best know as Pro-survival member of the BCL-2 family of proteins that regulate intrinsic apoptotic cascade. 3 MCL-1 is important for survival of most normal and malignant tissues. The C-terminal region of MCL-1 shares homology with the BCL-2 family of proteins, which contain four BCL-2homology-domains that form binding pockets for interaction with Pro-apoptotic BH3 only proteins and by doing so, protect normal and malignant cells from cell death. BCL-2 family members include two Pro-apoptotic subgroups: BH3-only sensor proteins, which trigger intrinsic apoptotic cascade in response to cytotoxic insults or cellular stresses and BAX and BAK, apoptotic effectors. BH domain hydrophobic pocket dictates MCL-1 binding specificity for BIM, tBID, PUMA, NOXA and BAK, thereby restraining cellular apoptotic activity.

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c-Myc

The Schematic illustration presents the functional model and regulation of FBXW7. Functional model of FBXW7. Schematic illustration show that SCF E3 ubiquitin ligase complex containing FBXW7 can target several important oncoproteins including C-Jun, C-MYC, and Notch1 et al for ubiquitylation. Regulation of FBXW7 from gene to protein. FBXW7 contains D-domain for dimer formation and two key domains of the F-box protein family including WD repeat and F-box for substrate binding and enzymatic activity. Regulatory mechanisms and related proteins that induce FBXW7 dysfunction at different levels. FBXW7, F-box / WD repeat-containing protein 7; RBX1, RING-box protein; KLF5, Kruppel-like factor 5; E2, enzyme 2; Ub, ubiquitin; Pi, phosphate; SKP1, S Phase kinase-associate protein 1; CUL1, cullin 1; Hes-5, hairy and enhancer of split 5; C / EBP-, CCAAT enhancer binding protein. Regulators and substrates of FBXW7 in human cancers. Several upstream proteins including EBP2, p53 and NUMB-4 can positively regulate FBXW7 while other upstream regulators including Pin1, Hes-5 and C / EBP etc. Can negatively regulate FBXW7. Specific substrates of FBXW7 including C-MYC, C-Jun and Mcl-1 can promote development of some tumors including lymphomas, intestinal cancer and hematological tumors. FBXW7, F-box / WD repeat-containing protein 7; EBP2, eIF4E-binding protein 2; C / EBP-, CCAAT enhancer binding protein; Pin1, peptidyl-prolyl cis-trans isomerase NIMA-interacting 1; Hes-5, hairy and enhancer of split 5; KLFs, Kruppel-like factor; T-ALL, T Cell acute lymphoblastic leukemia; Mcl-1, induce myeloid leukemia Cell differentiation protein Mcl-1. NUMB-4, NUMB endocytic adaptor protein. C-MYC is an important oncogenic protein that can regulate cell growth and division, serving a number of roles in human cancer. In lymphoid Tumor Cell lines, mutation of Thr58 site in C-MYC is the most frequent mutation and results in failure of FBXW7 to regulate C-MYC protein content, accumulation of C-MYC protein and eventual Tumor development. In addition to GSK3, NEMO-like kinase also regulates C-MYC protein content. NLK can directly bind to C-MYC and catalyze phosphorylation of multiple C-terminal sites. This modification promotes ubiquitination and proteasomal degradation of FBXW7. Mutation of these sites can abrogate C-MYC-FBXW7 Interaction and protein ubiquitination. Abnormal localization of C-MYC proteins can cause its accumulation and may lead to tumorigenesis. USP28 can bind to FBXW7 and inhibit ubiquitination modification of C-MYC by the latter, thus increasing the protein stability of C-MYC. DNA damage caused by ultraviolet radiation can reduce C-MYC protein content due to dissociation of USP28 and FBXW7, thus increasing FBXW7-mediate ubiquitination and degradation of C-MYC protein. Because both cyclin E and C-MYC are positive regulators of cell cycle, decreases in their levels can cause cell cycle exit. However, FBXW7 deficiency increases protein levels of these two factors and promotes cell cycle re-entry and G 1 / S Phase transition, which is conducive to cell division. This mechanism is an important reason for cancer driven by FBXW7 mutations.


Introduction

Protein-protein interactions are essential mediators of both physiologic and pathologic biology, yet, until recently, have been considered very challenging to target therapeutically with small molecules. Recent approval of protein-protein interaction inhibitory drugs such as venetoclax 1 2 and continuing clinical progression of others such as MDM2-TP53 antagonists 3 4 and BET bromodomain antagonists 5-7 demonstrate that certain types of protein-protein interactions can be effectively targeted with small molecules. A common feature of these druggable protein-protein interactions is the presence of a reasonably sized pocket or groove on the surface of the targeted protein that bind to the short peptide sequence of its respective interacting partner protein. Because these protein pockets have appropriate size, shape and physicochemical features to bind well to drug-like small molecules, latter can effectively compete for binding with physiological peptide regions of the target protein, thereby disrupting protein-protein interaction. Our greater appreciation of structural and chemical features of targetable PPIs together with increasing knowledge of functional protein interaction networks argue strongly that there are likely to be many more therapeutic opportunities embed in human protein interactome. The likelihood of exploiting these opportunities is enhanced by recent improvements in high throughput methods for screening of small molecules that bind to proteins, such as thermal stabilization 8, mass spectrometry detect affinity selection 9, DNA encode libraries 10 and high throughput fragment screening 11. Methods for directly screening for disruption of PPI have also advanced significantly over the past decade, including use of fluorescence polarization 12, and Alpha and NanoLuc technologies. Among the most abundant protein interaction domains in the human proteome is the WD40 repeat domain, with over 360 domains currently annotate. A WDR domain is typically a seven bladed-propeller domain with an overall donut shape. Significantly, donut hole or central pore of the WDR domain frequently mediates interactions with peptide regions of key interaction partners, and often has appropriate size and physicochemical features for high affinity binding to drug-like small molecules. WDR domains are often essential subunits of multiprotein complexes involved in a wide range of signaling pathways including DNA damage sensing and repair, ubiquitin signaling and protein degradation, cell cycle, epigenetic regulation of gene expression and chromatin organization, and immune related pathways. Here, we review recent progress and future opportunities for therapeutic targeting of human WDR proteins.

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mTOR

WD-repeat-containing proteins form a very large family that is diverse in both its function and domain structure. Within all these proteins, WD-repeat domains are thought to have two common features: domain folds into beta propeller; and domains form platform without any catalytic activity on which multiple protein complexes assemble reversibly. The fact that these proteins play such key roles in the formation of protein-protein complexes in nearly all major pathways and organelles unique to eukaryotic cells has two important implications. It supports both their ancient and proto eukaryotic origins and supports likely association with many genetic diseases.

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Sources

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