FBXO5

Last updated

FBXO5
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FBXO5 , EMI1, FBX5, Fbxo31, F-box protein 5
External IDs OMIM: 606013; MGI: 1914391; HomoloGene: 8135; GeneCards: FBXO5; OMA:FBXO5 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

26271

67141

Ensembl

ENSG00000112029

ENSMUSG00000019773

UniProt

Q9UKT4

Q7TSG3

RefSeq (mRNA)

NM_001142522
NM_012177

NM_025995

RefSeq (protein)

NP_001135994
NP_036309

NP_080271

Location (UCSC) Chr 6: 152.97 – 152.98 Mb Chr 10: 5.75 – 5.76 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

F-box only protein 5 is a protein that in humans is encoded by the FBXO5 gene. [5] [6] [7] The protein encoded by this gene belongs to the Fbxs class. This protein is similar to xenopus early mitotic inhibitor-1 (Emi1), which is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. [7] A more common term of FBXO5 is human EMI1. By primarily inhibiting Anaphase-Promoting Complex/Cyclosome (APC/C) activity, FBXO5/human EMI1 ensures timely mitotic entry. This protein is present in many organisms including Xenopus, zebrafish, Drosophila (homologous protein: Rca1), and humans. The findings illustrated here mainly focus on human EMI1, although it is likely that its function is conserved in other organisms.

Contents

Discovery and structure

EMI1 was first identified in a yeast two-hybrid screen [8] searching for proteins that bind to the SCF subunit Skp1. Several studies using Cryo-Electron Microscopy (Cryo-EM) and Nuclear Magnetic Resonance (NMR) Spectroscopy have revealed the structure and domains of EMI1 in humans that are key to its function in the inhibition of APC/C activity. [9] [10]

N-terminal domain

The N-terminal domain of EMI1 primarily consists of 244 amino acid residues. The use of Cryo-EM and AlphaFold prediction suggests that the N-terminal domain of EMI1 comprises a KEN box that allows for its interaction with CDH1WD40. [10] Although a previous study that utilized an in vitro binding assay demonstrates that the N-terminal domain of EMI1 does not bind to APC/C [11] , Höfler and colleagues propose that the binding of EMI1KEN motif with CDH1WD40 enhances the affinity of EMI1 for APC/CCDH1 while preventing KEN-box dependent binding of substrates to APC/C. [10]

F-box domain

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The F-box domain is responsible for the binding of EMI1 to SKP1, a subunit of the SCF ubiquitin ligase complex. [12]

C-terminal domain

The 143-residue C-terminal domain of EMI1 plays a critical role in its inhibitory function on APC/C. It contains intrinsically disordered D-box, Linker and Tail regions that are separated by a folded Zinc Binding Region (ZBR). [9] Both the D-box and ZBR are essential for the inhibitory function of EMI1 on APC/C E3 ligase activity. [11] The C-terminal RL tail of EMI1 is required for its binding and inhibition of APC/C. [13] Furthermore, the C-terminal tail of EMI1 suppresses the activity of ubiquitin-conjugating enzyme E2S (Ube2S), preventing its binding to APC. [9]

Regulators of human EMI1/FBXO5

Positive regulation by E2F Transcription Factor

EMI1 expression level is found to oscillate during the cell cycle, peaking during the G1 phase and diminishing in early mitosis. E2F transcription factor, a key regulator of the G1-S transition of the cell cycle, drives the expression of EMI1 as suggested by the increase in EMI1 transcription upon activation of E2F. [14]

Negative regulation by SCFβTrcp1, Polo-like kinase 1 (PLK-1) and Cyclin-Dependent Kinases (CDKs)

EMI1 is a substrate of β-Trcp1. The phosphorylation of EMI1 by cdc2 and phosphorylation on the DSGxxS motif mediates its recognition by SCFβTrcp1 ubiquitin ligase, targeting EMI1 for destruction. [15] [16] EMI1 is phosphorylated at serine-145 and serine-149 in the DSGxxS motif by PLK-1. siRNA-mediated inhibition of PLK-1 results in the prevalence of EMI1 for a longer period and a delay in entry to mitosis while overexpression of PLK-1 reduces the expression of EMI1. At lower concentrations of PLK-1, CDK1 plays a costimulatory/synergistic effect of PLK-1 dependent βTrcp recruitment by EMI1. [17] [18] Another study shows that by phosphorylating EMI1 during mitosis, CDKs reduce the ability of EMI1 to bind and inhibit APC/C, providing an alternative regulatory mechanism of EMI1 apart from ubiquitin-mediated EMI1 degradation. [19]

Role of hEMI1/FBXO5 in cell cycle progression

Inhibition of APC/C

EMI1 inhibits the activity of APC/C, a 1.2 MDa Ub ligase that plays a critical role in regulating the mitotic phase of the cell cycle by targeting mitotic regulators for degradation during mitotic exit. By inhibiting APC/C at the S and G2 phases of the cell cycle, EMI1 ensures a well-timed cell cycle progression and mitotic entry. EMI1 is believed to inhibit APC/C activity via multiple mechanisms executed by its various inhibitory domains. [20]

EMI1 inhibits APC/C activity both by competitive inhibition of substrate binding to APC/C and by inhibiting ubiquitylation. [21] The D-box of EMI1 inhibits the recruitment of APC/C substrates by competitively binding to the D-box receptor site of APC/CCdh1. [11] The ZBR of EMI1 prevents ubiquitylation of APC/C substrates by inhibiting UBCH10-mediated ubiquitin chain assembly and UBCH5-mediated monoubiquitylation. [21] The C-terminal tail of EMI1 blocks ubiquitin chain assembly by inhibiting ubiquitin-conjugating enzyme E2S (Ube2S) activity, preventing its binding to APC. [9] [21] Additionally, the C-terminal tail is involved in the recruitment of EMI1 to APC and the positioning of ZBR to block ubiquitin transfer. [21]

EMI1 plays an important role in maintaining the integrity and tight regulation of the cell cycle. The inhibition of APC/C by EMI1 in S and G2 phases ensures the stabilization of two regulators that prevent rereplication, cyclin A and geminin, and therefore maintains genomic integrity. [22] The importance of EMI1 in mitosis is further underscored in a study showcasing that failure of EMI1 degradation results in prometaphase block and mitotic catastrophe such as failure of chromosome congression and inhibition of cytokinesis. [15]

Dual role of hEMI1/FBXO5

Apart from being an inhibitor of APC/C, EMI1 acts as a substrate of APC/C where it is degraded by APC/CCdh1 in the G1 phase of the cell cycle. A model proposed by Cappell and colleagues suggests that EMI1 acts as a substrate at low concentrations and behaves as an inhibitor at concentrations higher than APC/CCdh1. The dual role of EMI1 creates an EMI1-APC/CCdh1 dual-negative feedback system, creating a bistable hysteretic switch that is often a key feature of irreversible cell cycle commitment. [23]

Implications in cancer and therapy

Dysregulation in the expression of EMI1 has been implicated in various cancer types. EMI1 is overexpressed in many solid cancers of various organs such as the esophagus, lung, breast, liver, ovary and bone. [24] [25] In colorectal cancer, loss of EMI1 expression causes chromosome instability, increases DNA double-stranded break, and causes cellular transformation such as an increase in proliferation and anchorage-independent growth. [26] Although these findings may seem conflicting, they suggest a possibility that EMI1 may play both an oncogenic and tumor-suppressive role in cancer. [26] Regardless, ensuring a well-regulated EMI1 expression is important in cancer prevention.

Notably, various studies have suggested that regulation of EMI1 expression may enhance the effectiveness of various cancer therapies. Reducing EMI1 expression increases the sensitivity of cancer cells to ionizing radiation and anticancer agents such as doxorubicin and camptothecin. [27] Conversely, reduction in EMI1 expression decreases the sensitivity of cancer cells to PARP inhibitor olaparib which is used to treat triple-negative breast cancer and thus, ensuring a sustained EMI1 expression is critical for effective cancer treatment. [12] A follow-up study shows that in cases of low EMI1 expression in BRCA1-mutant cells, cytotoxic drug CHK1 inhibitor could restore sensitivity to PARP inhibitor. [28]

Interactions

FBXO5 has been shown to interact with:

Related Research Articles

<span class="mw-page-title-main">Anaphase-promoting complex</span> Cell-cycle regulatory complex

Anaphase-promoting complex is an E3 ubiquitin ligase that marks target cell cycle proteins for degradation by the 26S proteasome. The APC/C is a large complex of 11–13 subunit proteins, including a cullin (Apc2) and RING (Apc11) subunit much like SCF. Other parts of the APC/C have unknown functions but are highly conserved.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another protein by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">Spindle checkpoint</span> Cell cycle checkpoint

The spindle checkpoint, also known as the metaphase-to-anaphase transition, the spindle assembly checkpoint (SAC), the metaphase checkpoint, or the mitotic checkpoint, is a cell cycle checkpoint during metaphase of mitosis or meiosis that prevents the separation of the duplicated chromosomes (anaphase) until each chromosome is properly attached to the spindle. To achieve proper segregation, the two kinetochores on the sister chromatids must be attached to opposite spindle poles. Only this pattern of attachment will ensure that each daughter cell receives one copy of the chromosome. The defining biochemical feature of this checkpoint is the stimulation of the anaphase-promoting complex by M-phase cyclin-CDK complexes, which in turn causes the proteolytic destruction of cyclins and proteins that hold the sister chromatids together.

Mad2 is an essential spindle checkpoint protein. The spindle checkpoint system is a regulatory system that restrains progression through the metaphase-to-anaphase transition. The Mad2 gene was first identified in the yeast S. cerevisiae in a screen for genes which when mutated would confer sensitivity to microtubule poisons. The human orthologues of Mad2 were first cloned in a search for human cDNAs that would rescue the microtubule poison-sensitivity of a yeast strain in which a kinetochore binding protein was missing. The protein was shown to be present at unattached kinetochores and antibody inhibition studies demonstrated it was essential to execute a block in the metaphase-to-anaphase transition in response to the microtubule poison nocodazole. Subsequent cloning of the Xenopus laevis orthologue, facilitated by the sharing of the human sequence, allowed for the characterization of the mitotic checkpoint in egg extracts.

<span class="mw-page-title-main">SCF complex</span>

Skp, Cullin, F-box containing complex is a multi-protein E3 ubiquitin ligase complex that catalyzes the ubiquitination of proteins destined for 26S proteasomal degradation. Along with the anaphase-promoting complex, SCF has important roles in the ubiquitination of proteins involved in the cell cycle. The SCF complex also marks various other cellular proteins for destruction.

Polo-like kinases (Plks) are regulatory serine/threonine kinases of the cell cycle involved in mitotic entry, mitotic exit, spindle formation, cytokinesis, and meiosis. Only one Plk is found in the genomes of the fly Drosophila melanogaster (Polo), budding yeast (Cdc5) and fission yeast (Plo1). Vertebrates and other animals, however, have many Plk family members including Plk1, Plk2/Snk, Plk3/Prk/FnK, Plk4/Sak and Plk5. Of the vertebrate Plk family members, the mammalian Plk1 has been most extensively studied. During mitosis and cytokinesis, Plks associate with several structures including the centrosome, kinetochores, and the central spindle.

<span class="mw-page-title-main">CDC20</span> Protein-coding gene in humans

The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate the anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase. The APC/CCdc20 protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows the cell to exit from mitosis. A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle.

<span class="mw-page-title-main">BTRC (gene)</span> Protein-coding gene in the species Homo sapiens

F-box/WD repeat-containing protein 1A (FBXW1A) also known as βTrCP1 or Fbxw1 or hsSlimb or pIkappaBalpha-E3 receptor subunit is a protein that in humans is encoded by the BTRC gene.

<span class="mw-page-title-main">CDC27</span> Protein-coding gene in humans

Cell division cycle protein 27 homolog is a protein that in humans is encoded by the CDC27 gene.

<span class="mw-page-title-main">FZR1</span> Protein-coding gene in humans

Fizzy-related protein homolog, also known as hCDH1, is a protein that in humans is encoded by the FZR1 gene.

<span class="mw-page-title-main">CDC16</span> Protein-coding gene in humans

Cell division cycle protein 16 homolog is a protein that in humans is encoded by the CDC16 gene.

<span class="mw-page-title-main">BUB3</span> Protein-coding gene in the species Homo sapiens

Mitotic checkpoint protein BUB3 is a protein that in humans is encoded by the BUB3 gene.

<span class="mw-page-title-main">ANAPC2</span> Protein-coding gene in the species Homo sapiens

Anaphase-promoting complex subunit 2 is an enzyme that in humans is encoded by the ANAPC2 gene.

<span class="mw-page-title-main">FBXW11</span> Protein-coding gene in the species Homo sapiens

βTrCP2 is a protein that in humans is encoded by the FBXW11 gene.

<span class="mw-page-title-main">Cell division control protein 4</span>

Cdc4 is a substrate recognition component of the SCF ubiquitin ligase complex, which acts as a mediator of ubiquitin transfer to target proteins, leading to their subsequent degradation via the ubiquitin-proteasome pathway. Cdc4 targets primarily cell cycle regulators for proteolysis. It serves the function of an adaptor that brings target molecules to the core SCF complex. Cdc4 was originally identified in the model organism Saccharomyces cerevisiae. CDC4 gene function is required at G1/S and G2/M transitions during mitosis and at various stages during meiosis.

<span class="mw-page-title-main">Mad1</span>

Mad1 is a non-essential protein which in yeast has a function in the spindle assembly checkpoint (SAC). This checkpoint monitors chromosome attachment to spindle microtubules and prevents cells from starting anaphase until the spindle is built up. The name Mad refers to the observation that mutant cells are mitotic arrest deficient (MAD) during microtubule depolymerization. Mad1 recruits the anaphase inhibitor Mad2 to unattached kinetochores and is essential for Mad2-Cdc20 complex formation in vivo but not in vitro. In vivo, Mad1 acts as a competitive inhibitor of the Mad2-Cdc20 complex. Mad1 is phosphorylated by Mps1 which then leads together with other activities to the formation of the mitotic checkpoint complex (MCC). Thereby it inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C). Homologues of Mad1 are conserved in eukaryotes from yeast to mammals.

<span class="mw-page-title-main">APC/C activator protein CDH1</span> Fungal protein found in Saccharomyces cerevisiae S288c

Cdh1 is one of the substrate adaptor proteins of the anaphase-promoting complex (APC) in the budding yeast Saccharomyces cerevisiae. Functioning as an activator of the APC/C, Cdh1 regulates the activity and substrate specificity of this ubiquitin E3-ligase. The human homolog is encoded by the FZR1 gene, which is not to be confused with the CDH1 gene.

Mitotic exit is an important transition point that signifies the end of mitosis and the onset of new G1 phase for a cell, and the cell needs to rely on specific control mechanisms to ensure that once it exits mitosis, it never returns to mitosis until it has gone through G1, S, and G2 phases and passed all the necessary checkpoints. Many factors including cyclins, cyclin-dependent kinases (CDKs), ubiquitin ligases, inhibitors of cyclin-dependent kinases, and reversible phosphorylations regulate mitotic exit to ensure that cell cycle events occur in correct order with fewest errors. The end of mitosis is characterized by spindle breakdown, shortened kinetochore microtubules, and pronounced outgrowth of astral (non-kinetochore) microtubules. For a normal eukaryotic cell, mitotic exit is irreversible.

<span class="mw-page-title-main">Motifs targeted by APC/C</span>

The anaphase- promoting complex or cyclosome (APC/C) is a highly specific ubiquitin protein ligase responsible for triggering events of late mitosis. In early mitosis, Cdc20 levels rise and APC/C binds to form active APC/CCdc20. This then leads to the destruction of mitotic cyclins, securin, and other proteins to trigger chromosome separation in anaphase. In early anaphase, Cdk1 is inactivated, leading to the activation of Cdh1, the other activator subunit of APC/C. This then triggers the degradation of Cdc20 and leads to the activation of APC/CCdh1 through G1 to suppress S- phase cyclin-Cdk activity. At the end of G1, APC/CCdh1 is inactivated and S- phase and mitotic cyclins gets reaccumulate as the cell progresses to S phase.

Early Mitotic Inhibitor 1 (EMI1) is an important cell cycle regulator which ensures timely mitotic entry by primarily inhibiting Anaphase-Promoting Complex/Cyclosome (APC/C) activity. This protein is present in many organisms including Xenopus, Zebrafish, Drosophila, and Humans. The findings illustrated here mainly focus on human EMI1, although it is likely that its function is conserved in other organisms.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000112029 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000019773 – Ensembl, May 2017
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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  19. ↑ Moshe Y, Bar-On O, Ganoth D, Hershko A (2011-05-13). "Regulation of the Action of Early Mitotic Inhibitor 1 on the Anaphase-promoting Complex/Cyclosome by Cyclin-dependent Kinases *". Journal of Biological Chemistry. 286 (19): 16647–16657. doi: 10.1074/jbc.M111.223339 . ISSN   0021-9258. PMC   3089507 . PMID   21454540.
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  27. ↑ Shimizu N, Nakajima NI, Tsunematsu T, Ogawa I, Kawai H, Hirayama R, et al. (2013-06-14). "Selective Enhancing Effect of Early Mitotic Inhibitor 1 (Emi1) Depletion on the Sensitivity of Doxorubicin or X-ray Treatment in Human Cancer Cells". Journal of Biological Chemistry. 288 (24): 17238–17252. doi: 10.1074/jbc.M112.446351 . ISSN   0021-9258. PMC   3682528 . PMID   23645673.
  28. ↑ Moustafa D, Elwahed MR, Elsaid HH, Parvin JD (2021-01-07). "Modulation of Early Mitotic Inhibitor 1 (EMI1) depletion on the sensitivity of PARP inhibitors in BRCA1 mutated triple-negative breast cancer cells". PLOS ONE. 16 (1): e0235025. doi: 10.1371/journal.pone.0235025 . ISSN   1932-6203. PMC   7790533 . PMID   33412559.
  29. ↑ Cenciarelli C, Chiaur DS, Guardavaccaro D, Parks W, Vidal M, Pagano M (October 1999). "Identification of a family of human F-box proteins". Current Biology. 9 (20): 1177–9. Bibcode:1999CBio....9.1177C. doi: 10.1016/S0960-9822(00)80020-2 . PMID   10531035. S2CID   7467493.

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