Q9UKC9 · FBXL2_HUMAN
- ProteinF-box/LRR-repeat protein 2
- GeneFBXL2
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids423 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Calcium-activated substrate recognition component of the SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex, SCF(FBXL2), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:22020328, PubMed:22323446).
Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin (PubMed:22020328, PubMed:22323446).
This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin (PubMed:22020328, PubMed:22323446).
Through CCND2 and CCND3 degradation induces cell-cycle arrest in G0 (PubMed:22020328, PubMed:22323446).
SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy (PubMed:23604317).
PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant (By similarity).
The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6) (By similarity).
The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3 (PubMed:26037928).
Unlike many F-box proteins, FBXL2 does not seem to target phosphodegron within its substrates but rather calmodulin-binding motifs and is thereby antagonized by calmodulin (PubMed:22020328, PubMed:22323446).
This is the case for the cyclins CCND2 and CCND3 which polyubiquitination and subsequent degradation are inhibited by calmodulin (PubMed:22020328, PubMed:22323446).
Through CCND2 and CCND3 degradation induces cell-cycle arrest in G0 (PubMed:22020328, PubMed:22323446).
SCF(FBXL2) also mediates PIK3R2 ubiquitination and proteasomal degradation thereby regulating phosphatidylinositol 3-kinase signaling and autophagy (PubMed:23604317).
PCYT1A monoubiquitination by SCF(FBXL2) and subsequent degradation regulates synthesis of phosphatidylcholine, which is utilized for formation of membranes and of pulmonary surfactant (By similarity).
The SCF(FBXL2) complex acts as a regulator of inflammation by mediating ubiquitination and degradation of TRAF proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5 and TRAF6) (By similarity).
The SCF(FBXL2) complex acts as a negative regulator of the NLRP3 inflammasome by mediating ubiquitination and degradation of NLRP3 (PubMed:26037928).
Miscellaneous
Deletion of the F-box domain creates a dominant-negative protein that inhibits replication of hepatitis C virus RNA when overexpressed in a hepatoma cell line; this inhibition could be overcome by NS5A coexpression.
Pathway
Protein modification; protein ubiquitination.
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | cytoplasm | |
Cellular Component | membrane | |
Cellular Component | SCF ubiquitin ligase complex | |
Molecular Function | calmodulin binding | |
Molecular Function | phosphatidylinositol 3-kinase regulatory subunit binding | |
Molecular Function | protein phosphatase binding | |
Molecular Function | ubiquitin-like ligase-substrate adaptor activity | |
Biological Process | modulation by host of viral RNA genome replication | |
Biological Process | negative regulation of NLRP3 inflammasome complex assembly | |
Biological Process | protein modification process | |
Biological Process | protein monoubiquitination | |
Biological Process | protein ubiquitination | |
Biological Process | proteolysis | |
Biological Process | regulation of autophagy | |
Biological Process | regulation of inflammatory response | |
Biological Process | regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | |
Biological Process | SCF-dependent proteasomal ubiquitin-dependent protein catabolic process |
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameF-box/LRR-repeat protein 2
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionQ9UKC9
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_036071 | 226 | in a colorectal cancer sample; somatic mutation | |||
Sequence: V → M | ||||||
Mutagenesis | 420 | Loss of geranylgeranylation and association to membranes. Loss of interaction with NS5A, PIK3R1 and PIK3R2. No effect on interaction with PTPN13. | ||||
Sequence: C → S |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 339 variants from UniProt as well as other sources including ClinVar and dbSNP.
Organism-specific databases
Miscellaneous
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), cross-link, modified residue, lipidation.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000119840 | 1-423 | UniProt | F-box/LRR-repeat protein 2 | |||
Sequence: MVFSNNDEGLINKKLPKELLLRIFSFLDIVTLCRCAQISKAWNILALDGSNWQRIDLFNFQTDVEGRVVENISKRCGGFLRKLSLRGCIGVGDSSLKTFAQNCRNIEHLNLNGCTKITDSTCYSLSRFCSKLKHLDLTSCVSITNSSLKGISEGCRNLEYLNLSWCDQITKDGIEALVRGCRGLKALLLRGCTQLEDEALKHIQNYCHELVSLNLQSCSRITDEGVVQICRGCHRLQALCLSGCSNLTDASLTALGLNCPRLQILEAARCSHLTDAGFTLLARNCHELEKMDLEECILITDSTLIQLSIHCPKLQALSLSHCELITDDGILHLSNSTCGHERLRVLELDNCLLITDVALEHLENCRGLERLELYDCQQVTRAGIKRMRAQLPHVKVHAYFAPVTPPTAVAGSGQRLCRCCVIL | |||||||
Modified residue (large scale data) | 4 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Cross-link | 201 | UniProt | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | |||||||
Modified residue | 404 | UniProt | Phosphothreonine | ||||
Sequence: T | |||||||
Modified residue (large scale data) | 404 | PRIDE | Phosphothreonine | ||||
Sequence: T | |||||||
Lipidation | 420 | UniProt | S-geranylgeranyl cysteine | ||||
Sequence: C |
Post-translational modification
Phosphorylated by GSK-beta (GSK3B), promoting recognition by FBXO3, leading to its ubiquitination by the SCF(FBXO3) complex.
Ubiquitinated at Lys-201 by the SCF(FBXO3) complex in response to lipopolysaccharide (LPS), leading to its degradation by the proteasome.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
Expressed in brain, heart, kidney, liver, lung, pancreas and placenta.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXL2) composed of CUL1, SKP1, RBX1 and FBXL2 (PubMed:10531037).
Interacts with calmodulin; may antagonize substrate ubiquitination by SCF(FBXL2) (PubMed:22020328).
May interact with PIK3R1 (PubMed:23604317).
Interacts with PTPN13 (PubMed:23604317).
Interacts with calmodulin; may antagonize substrate ubiquitination by SCF(FBXL2) (PubMed:22020328).
May interact with PIK3R1 (PubMed:23604317).
Interacts with PTPN13 (PubMed:23604317).
(Microbial infection) Interacts with hepatitis C virus non-structural protein 5A (NS5A) and less efficiently, with hepatitis C virus non-structural protein 5B (NS5B); a reaction crucial for hepatitis C virus RNA replication.
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | Q9UKC9 | CCT5 P48643 | 3 | EBI-724253, EBI-355710 | |
BINARY | Q9UKC9 | HSP90AB1 P08238 | 2 | EBI-724253, EBI-352572 | |
BINARY | Q9UKC9 | SKP1 P63208 | 9 | EBI-724253, EBI-307486 |
Protein-protein interaction databases
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, repeat, region, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 9-55 | F-box | ||||
Sequence: GLINKKLPKELLLRIFSFLDIVTLCRCAQISKAWNILALDGSNWQRI | ||||||
Repeat | 61-87 | LRR 1 | ||||
Sequence: QTDVEGRVVENISKRCGGFLRKLSLRG | ||||||
Region | 80-90 | Interaction with Calmodulin | ||||
Sequence: LRKLSLRGCIG | ||||||
Repeat | 88-113 | LRR 2 | ||||
Sequence: CIGVGDSSLKTFAQNCRNIEHLNLNG | ||||||
Repeat | 114-139 | LRR 3 | ||||
Sequence: CTKITDSTCYSLSRFCSKLKHLDLTS | ||||||
Repeat | 140-165 | LRR 4 | ||||
Sequence: CVSITNSSLKGISEGCRNLEYLNLSW | ||||||
Repeat | 166-191 | LRR 5 | ||||
Sequence: CDQITKDGIEALVRGCRGLKALLLRG | ||||||
Repeat | 192-217 | LRR 6 | ||||
Sequence: CTQLEDEALKHIQNYCHELVSLNLQS | ||||||
Repeat | 218-243 | LRR 7 | ||||
Sequence: CSRITDEGVVQICRGCHRLQALCLSG | ||||||
Repeat | 244-269 | LRR 8 | ||||
Sequence: CSNLTDASLTALGLNCPRLQILEAAR | ||||||
Repeat | 270-295 | LRR 9 | ||||
Sequence: CSHLTDAGFTLLARNCHELEKMDLEE | ||||||
Repeat | 296-321 | LRR 10 | ||||
Sequence: CILITDSTLIQLSIHCPKLQALSLSH | ||||||
Repeat | 322-350 | LRR 11 | ||||
Sequence: CELITDDGILHLSNSTCGHERLRVLELDN | ||||||
Repeat | 351-375 | LRR 12 | ||||
Sequence: CLLITDVALEHLENCRGLERLELYD | ||||||
Repeat | 376-401 | LRR 13 | ||||
Sequence: CQQVTRAGIKRMRAQLPHVKVHAYFA | ||||||
Motif | 420-423 | CAAX motif | ||||
Sequence: CVIL |
Domain
The CAAX motif is a signal for the geranylgeranylation of FBXL2 and is required for its association with cell membranes and the recruitment of substrates to the active SCF(FBXL2) complex.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
Q9UKC9-1
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
- Length423
- Mass (Da)47,062
- Last updated2007-04-17 v3
- Checksum61938E434618BA3D
Q9UKC9-2
- Name2
- Differences from canonical
- 132-199: Missing
Computationally mapped potential isoform sequences
There are 6 potential isoforms mapped to this entry
Sequence caution
Features
Showing features for sequence conflict, alternative sequence.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 62 | in Ref. 1; AAF04510, 2; AAF03128 and 5; CAG33402 | ||||
Sequence: T → I | ||||||
Sequence conflict | 77 | in Ref. 1; AAF04510 | ||||
Sequence: G → V | ||||||
Sequence conflict | 81 | in Ref. 4; BAA91691 | ||||
Sequence: R → K | ||||||
Sequence conflict | 108 | in Ref. 4; BAG61062 | ||||
Sequence: H → Q | ||||||
Alternative sequence | VSP_044600 | 132-199 | in isoform 2 | |||
Sequence: Missing | ||||||
Sequence conflict | 174 | in Ref. 8; CAB43222 | ||||
Sequence: I → W | ||||||
Sequence conflict | 320 | in Ref. 8; CAB43222 | ||||
Sequence: S → P | ||||||
Sequence conflict | 342 | in Ref. 5; CAG33402 | ||||
Sequence: R → G |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
AF174589 EMBL· GenBank· DDBJ | AAF04510.1 EMBL· GenBank· DDBJ | mRNA | ||
AF176518 EMBL· GenBank· DDBJ | AAF03128.1 EMBL· GenBank· DDBJ | mRNA | Different initiation | |
AF186273 EMBL· GenBank· DDBJ | AAD56248.1 EMBL· GenBank· DDBJ | mRNA | ||
AK001438 EMBL· GenBank· DDBJ | BAA91691.1 EMBL· GenBank· DDBJ | mRNA | ||
AK298967 EMBL· GenBank· DDBJ | BAG61062.1 EMBL· GenBank· DDBJ | mRNA | ||
CR457121 EMBL· GenBank· DDBJ | CAG33402.1 EMBL· GenBank· DDBJ | mRNA | ||
AC122176 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AC123900 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC031556 EMBL· GenBank· DDBJ | AAH31556.1 EMBL· GenBank· DDBJ | mRNA | ||
AL049953 EMBL· GenBank· DDBJ | CAB43222.1 EMBL· GenBank· DDBJ | mRNA |