Q8C2S5 · FBXL5_MOUSE
- ProteinF-box/LRR-repeat protein 5
- GeneFbxl5
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids690 (go to sequence)
- Protein existenceEvidence at transcript level
- Annotation score5/5
Function
function
Component of some SCF (SKP1-cullin-F-box) protein ligase complex that plays a central role in iron homeostasis by promoting the ubiquitination and subsequent degradation of IREB2/IRP2 (PubMed:21907140, PubMed:23135277).
The C-terminal domain of FBXL5 contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, promotes binding to IRP2 to effect its oxygen-dependent degradation. Under iron deficiency conditions, the N-terminal hemerythrin-like (Hr) region, which contains a diiron metal center, cannot bind iron and undergoes conformational changes that destabilize the FBXL5 protein and cause its ubiquitination and degradation. When intracellular iron levels start rising, the Hr region is stabilized. Additional increases in iron levels facilitate the assembly and incorporation of a redox active [2Fe-2S] cluster in the C-terminal domain. Only when oxygen level is high enough to maintain the cluster in its oxidized state can FBXL5 recruit IRP2 as a substrate for polyubiquination and degradation. Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1. Within the nucleus, promotes the ubiquitination of SNAI1; preventing its interaction with DNA and promoting its degradation. Negatively regulates DNA damage response by mediating the ubiquitin-proteasome degradation of the DNA repair protein NABP2 (By similarity).
The C-terminal domain of FBXL5 contains a redox-sensitive [2Fe-2S] cluster that, upon oxidation, promotes binding to IRP2 to effect its oxygen-dependent degradation. Under iron deficiency conditions, the N-terminal hemerythrin-like (Hr) region, which contains a diiron metal center, cannot bind iron and undergoes conformational changes that destabilize the FBXL5 protein and cause its ubiquitination and degradation. When intracellular iron levels start rising, the Hr region is stabilized. Additional increases in iron levels facilitate the assembly and incorporation of a redox active [2Fe-2S] cluster in the C-terminal domain. Only when oxygen level is high enough to maintain the cluster in its oxidized state can FBXL5 recruit IRP2 as a substrate for polyubiquination and degradation. Promotes ubiquitination and subsequent degradation of the dynactin complex component DCTN1. Within the nucleus, promotes the ubiquitination of SNAI1; preventing its interaction with DNA and promoting its degradation. Negatively regulates DNA damage response by mediating the ubiquitin-proteasome degradation of the DNA repair protein NABP2 (By similarity).
Cofactor
Activity regulation
An iron-sulfur cluster promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.
Pathway
Protein modification; protein ubiquitination.
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 15 | Fe3+ 1 (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 57 | Fe3+ 1 (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 58 | Fe3+ 2 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 61 | Fe3+ 1 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 61 | Fe3+ 2 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 80 | Fe3+ 2 (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 126 | Fe3+ 2 (UniProtKB | ChEBI) | ||||
Sequence: H | ||||||
Binding site | 130 | Fe3+ 1 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 130 | Fe3+ 2 (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 661 | [2Fe-2S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 675 | [2Fe-2S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 685 | [2Fe-2S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C | ||||||
Binding site | 686 | [2Fe-2S] cluster (UniProtKB | ChEBI) | ||||
Sequence: C |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | nucleus | |
Cellular Component | perinuclear region of cytoplasm | |
Cellular Component | SCF ubiquitin ligase complex | |
Molecular Function | iron ion binding | |
Molecular Function | iron-sulfur cluster binding | |
Biological Process | intracellular iron ion homeostasis | |
Biological Process | multicellular organismal-level iron ion homeostasis | |
Biological Process | positive regulation of protein catabolic process | |
Biological Process | protein catabolic process | |
Biological Process | protein ubiquitination | |
Biological Process | SCF-dependent proteasomal ubiquitin-dependent protein catabolic process |
Keywords
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameF-box/LRR-repeat protein 5
- Alternative names
Gene names
Organism names
- Organism
- Strains
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Mus > Mus
Accessions
- Primary accessionQ8C2S5
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Phenotypes & Variants
Disruption phenotype
FBXL5-deletion mice die during early embryogenesis (PubMed:21907140, PubMed:23135277).
FBXL5-null embryos accumulate excess ferrous iron and are exposed to damaging levels of oxidative stress (PubMed:21907140).
Simultaneous inactivation of both the FBXL5 and IRP2 genes is sufficient to rescue embryonic lethality (PubMed:21907140).
FBXL5-null embryos accumulate excess ferrous iron and are exposed to damaging levels of oxidative stress (PubMed:21907140).
Simultaneous inactivation of both the FBXL5 and IRP2 genes is sufficient to rescue embryonic lethality (PubMed:21907140).
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 20 variants from UniProt as well as other sources including ClinVar and dbSNP.
PTM/Processing
Features
Showing features for chain.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000119846 | 1-690 | F-box/LRR-repeat protein 5 | |||
Sequence: MAPFPDEVDVFTAPHWRMKQLVGRYCDKLSKTNFSNNNDFRALLQSLYATFKEFKMHEQIENEYIIGLLQQRSQTIYNVHSDNKLSEMLSLFEKGLKNVKNEYEQLNYAKQLKERLEAFTRDFLPHMKEEEEVFQPMLMEYFTYEELKDIKKKVIAQHCSQKDTAELLRGLSLWNQAEERQKVLKYSVDEKADTEAEVSEHSTGITHLPPEVMLSIFSYLNPQELCRCSQVSTKWSQLAKTGSLWKHLYPVHWARGDWYSGPATELDTEPDEEWVRNRKDESRAFQEWDEDADIDESEESAEESVAISIAQMEKRVLHGLIHNVLPYVGTSVKTLVLAYSSAVSSKMVRQILELCPNLEHLDLTQTDISDSAFDSWSWLGCCQSLRHLDLSGCEKITDMALEKISRALGVLTSHQSGFLKSAGKAASTPWTSKDITMPSTTQYACLHNLTDKGIGEEIDNEHSWTEPVSSESLTSPYVWMLDAEDLADIEDAVEWRHRNVESLCVMETASNFGCSSSGCYSKDIVGLRTSVCWQQHCASPAFAYCGHSFCCTGTALRTMTTLPATSAMCRKALRTTLPRGKDLIYFGSEKSDQETGRVLLFLSLSGCYQITDHGLRALTLGGGLPYLEHLNLSGCLTVTGAGLQDLVSACPSLNDEYFYYCDNINGPHADTASGCQNLQCGFRACCRSGE |
Post-translational modification
Polybiquitinated upon iron and oxygen depletion, leading to its degradation by the proteasome. Ubiquitination is regulated by the hemerythrin-like region that acts as an oxygen and iron sensor. Undergoes constitutive ubiquitin-dependent degradation at the steady state by HERC2.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Ubiquitously expressed. Highly expressed in early embryogenesis with expression decreasing as the embryo progresses through development (E11 and E15).
Gene expression databases
Structure
Family & Domains
Features
Showing features for region, domain, repeat.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-159 | Hemerythrin-like | ||||
Sequence: MAPFPDEVDVFTAPHWRMKQLVGRYCDKLSKTNFSNNNDFRALLQSLYATFKEFKMHEQIENEYIIGLLQQRSQTIYNVHSDNKLSEMLSLFEKGLKNVKNEYEQLNYAKQLKERLEAFTRDFLPHMKEEEEVFQPMLMEYFTYEELKDIKKKVIAQHC | ||||||
Domain | 202-248 | F-box | ||||
Sequence: STGITHLPPEVMLSIFSYLNPQELCRCSQVSTKWSQLAKTGSLWKHL | ||||||
Repeat | 340-364 | LRR 1 | ||||
Sequence: SSAVSSKMVRQILELCPNLEHLDLT | ||||||
Repeat | 365-392 | LRR 2 | ||||
Sequence: QTDISDSAFDSWSWLGCCQSLRHLDLSG | ||||||
Repeat | 393-418 | LRR 3 | ||||
Sequence: CEKITDMALEKISRALGVLTSHQSGF | ||||||
Repeat | 478-507 | LRR 4 | ||||
Sequence: VWMLDAEDLADIEDAVEWRHRNVESLCVME | ||||||
Repeat | 575-606 | LRR 5 | ||||
Sequence: TTLPRGKDLIYFGSEKSDQETGRVLLFLSLSG | ||||||
Repeat | 607-634 | LRR 6 | ||||
Sequence: CYQITDHGLRALTLGGGLPYLEHLNLSG | ||||||
Repeat | 635-660 | LRR 7 | ||||
Sequence: CLTVTGAGLQDLVSACPSLNDEYFYY |
Domain
The hemerythrin-like region acts as an oxygen and iron sensor by binding oxygen through a diiron metal-center. In absence of oxygen and iron, the protein is ubiquitinated and degraded (By similarity).
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoforms
- Sequence statusComplete
This entry describes 5 isoforms produced by Alternative splicing.
Q8C2S5-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Length690
- Mass (Da)77,894
- Last updated2003-10-03 v2
- Checksum9558476AFB3ECCA0
Q8C2S5-2
- Name2
- Differences from canonical
- 1-28: MAPFPDEVDVFTAPHWRMKQLVGRYCDK → MRNNQELKYEIKWKHLDCSVVE
Q8C2S5-3
- Name3
Q8C2S5-4
- Name4
- Differences from canonical
- 298-298: Missing
Q8C2S5-5
- Name5
Computationally mapped potential isoform sequences
There are 4 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
D3Z584 | D3Z584_MOUSE | Fbxl5 | 673 | ||
F7BZC4 | F7BZC4_MOUSE | Fbxl5 | 679 | ||
F6W6I1 | F6W6I1_MOUSE | Fbxl5 | 611 | ||
A0A0G2JE06 | A0A0G2JE06_MOUSE | Fbxl5 | 107 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_008418 | 1-28 | in isoform 2 | |||
Sequence: MAPFPDEVDVFTAPHWRMKQLVGRYCDK → MRNNQELKYEIKWKHLDCSVVE | ||||||
Alternative sequence | VSP_038529 | 29-71 | in isoform 5 | |||
Sequence: Missing | ||||||
Sequence conflict | 105 | in Ref. 1; BAC38698 | ||||
Sequence: Q → R | ||||||
Sequence conflict | 127 | in Ref. 1; BAC40126 | ||||
Sequence: M → K | ||||||
Alternative sequence | VSP_038530 | 298 | in isoform 4 | |||
Sequence: Missing | ||||||
Alternative sequence | VSP_008419 | 617-623 | in isoform 3 and isoform 5 | |||
Sequence: ALTLGGG → WVISPSC | ||||||
Alternative sequence | VSP_008420 | 624-690 | in isoform 3 and isoform 5 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AK029957 EMBL· GenBank· DDBJ | BAC26698.1 EMBL· GenBank· DDBJ | mRNA | ||
AK041497 EMBL· GenBank· DDBJ | BAC30964.1 EMBL· GenBank· DDBJ | mRNA | ||
AK082931 EMBL· GenBank· DDBJ | BAC38698.1 EMBL· GenBank· DDBJ | mRNA | ||
AK085100 EMBL· GenBank· DDBJ | BAC39366.1 EMBL· GenBank· DDBJ | mRNA | ||
AK088067 EMBL· GenBank· DDBJ | BAC40126.1 EMBL· GenBank· DDBJ | mRNA | ||
AK150664 EMBL· GenBank· DDBJ | BAE29748.1 EMBL· GenBank· DDBJ | mRNA | ||
AK159744 EMBL· GenBank· DDBJ | BAE35337.1 EMBL· GenBank· DDBJ | mRNA | ||
AK171783 EMBL· GenBank· DDBJ | BAE42662.1 EMBL· GenBank· DDBJ | mRNA | ||
BC047214 EMBL· GenBank· DDBJ | AAH47214.1 EMBL· GenBank· DDBJ | mRNA | ||
BC113798 EMBL· GenBank· DDBJ | AAI13799.1 EMBL· GenBank· DDBJ | mRNA |