FBXO33

Summary

FBXO33 (F-box protein 33, HGNC:19833) is a protein-coding gene on chromosome 14q21.1, encoding F-box only protein 33 (Q7Z6M2). Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This locus represents an member of the F-box gene family. The encoded protein contains an F-box motif and a domain that might form a structure similar to a leucine-rich repeat found in placental RNAse inhibitor. This locus may be associated with copy number variation of UGT2B17 (GeneID 7367), which has been associated with susceptibility to osteoporosis.

Source: NCBI Gene 254170 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 98 total
• MANE Select transcript: NM_203301

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19833
Approved symbol	FBXO33
Name	F-box protein 33
Location	14q21.1
Locus type	gene with protein product
Status	Approved
Aliases	Fbx33
Ensembl gene	ENSG00000165355
Ensembl biotype	protein_coding
OMIM	609103
Entrez	254170

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000298097, ENST00000554190, ENST00000554932, ENST00000934503

RefSeq mRNA: 1 — MANE Select: NM_203301 NM_203301

CCDS: CCDS9677

Canonical transcript exons

ENST00000298097 — 4 exons

Exon	Start	End
ENSE00001092471	39402401	39402511
ENSE00001092483	39401176	39401861
ENSE00001256315	39397684	39399787
ENSE00001256320	39431564	39432433

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 97.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4293 / max 345.1260, expressed in 1771 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
143021	6.4254	1624
143022	4.0534	1607
143020	1.7308	711
207205	0.2196	61

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	97.25	gold quality
oocyte	CL:0000023	93.90	gold quality
buccal mucosa cell	CL:0002336	93.82	gold quality
sperm	CL:0000019	91.32	gold quality
Brodmann (1909) area 23	UBERON:0013554	90.27	gold quality
pancreatic ductal cell	CL:0002079	89.93	silver quality
middle temporal gyrus	UBERON:0002771	89.21	gold quality
lateral nuclear group of thalamus	UBERON:0002736	89.09	gold quality
parietal lobe	UBERON:0001872	88.89	gold quality
postcentral gyrus	UBERON:0002581	88.67	gold quality
thymus	UBERON:0002370	88.03	gold quality
epithelial cell of pancreas	CL:0000083	87.94	gold quality
occipital lobe	UBERON:0002021	87.93	gold quality
primary visual cortex	UBERON:0002436	87.51	gold quality
superior frontal gyrus	UBERON:0002661	87.40	gold quality
bone marrow	UBERON:0002371	86.36	gold quality
substantia nigra pars compacta	UBERON:0001965	86.32	gold quality
oviduct epithelium	UBERON:0004804	86.29	gold quality
ileal mucosa	UBERON:0000331	85.99	gold quality
palpebral conjunctiva	UBERON:0001812	85.88	gold quality
lateral globus pallidus	UBERON:0002476	85.87	gold quality
pons	UBERON:0000988	85.64	gold quality
eye	UBERON:0000970	85.61	gold quality
islet of Langerhans	UBERON:0000006	85.06	gold quality
seminal vesicle	UBERON:0000998	84.86	gold quality
pigmented layer of retina	UBERON:0001782	84.81	gold quality
cerebellar vermis	UBERON:0004720	84.80	silver quality
medulla oblongata	UBERON:0001896	84.51	gold quality
superior vestibular nucleus	UBERON:0007227	84.47	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.45	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	288.65
E-GEOD-124858	no	44.35
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

318 targeting FBXO33, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4803	99.98	71.99	3117

Literature-anchored findings (GeneRIF, showing 2)

• This study findings show tentative evidence for the involvement of FBXO33 in the susceptibility to adult attention-deficit hyperactivity disorder. (PMID:25284319)
• Quantitative and Qualitative Role of Antagonistic Heterogeneity in Genetics of Blood Lipids. (PMID:31566214)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fbxo33	ENSDARG00000075400
mus_musculus	Fbxo33	ENSMUSG00000035329
rattus_norvegicus	Fbxo33	ENSRNOG00000005285
drosophila_melanogaster	CG4911	FBGN0035959

Protein

Protein identifiers

F-box only protein 33 — Q7Z6M2 (reviewed: Q7Z6M2)

All UniProt accessions (2): Q7Z6M2, G3V3J7

UniProt curated annotations — full annotation on UniProt →

Function. Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Probably recognizes and binds to phosphorylated target proteins. Recognizes YBX1.

Subunit / interactions. Part of the SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complex SCF(FBXO33) formed of CUL1, SKP1, RBX1 and FBXO33. Interacts via its N-terminus with YBX1 CSD domain. Directly interacts with SKP1 and CUL1.

Pathway. Protein modification; protein ubiquitination.

RefSeq proteins (1): NP_976046* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001810	F-box_dom	Domain
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036047	F-box-like_dom_sf	Homologous_superfamily

Pfam: PF12937

UniProt features (2 total): chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z6M2-F1	82.54	0.64

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 265 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, ATGTTAA_MIR302C, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM5, ATF1_Q6, CAATGCA_MIR33, ACATTCC_MIR1_MIR206, ATTCTTT_MIR186, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, ATGCTGG_MIR338, TCCAGAT_MIR5165P, GOBP_SCF_DEPENDENT_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, DING_LUNG_CANCER_EXPRESSION_BY_COPY_NUMBER

GO Biological Process (2): protein ubiquitination (GO:0016567), positive regulation of protein ubiquitination (GO:0031398)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein modification by small protein conjugation	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
binding	1

Protein interactions and networks

STRING

574 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FBXO33	RNH1	P13489	826
FBXO33	CUL1	Q13616	750
FBXO33	TRIM75	A6NK02	611
FBXO33	FBXO25	Q8TCJ0	589
FBXO33	LRFN5	Q96NI6	555
FBXO33	Q8WV35	Q8WV35	528
FBXO33	SKP1	P34991	527
FBXO33	FBXL15	Q9H469	507
FBXO33	AMN1	Q8IY45	506
FBXO33	WDR47	O94967	506
FBXO33	TRAPPC6B	Q86SZ2	488
FBXO33	ZNF891	A8MT65	479
FBXO33	PACRG	Q96M98	478
FBXO33	FBXO11	Q86XK2	475
FBXO33	FBXL14	Q8N1E6	470

IntAct

35 interactions, top by confidence:

A	B	Type	Score
FBXO33	SKP1	psi-mi:“MI:0915”(physical association)	0.740
YBX1	SSB	psi-mi:“MI:0914”(association)	0.710
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
SKP1	MYCBP2	psi-mi:“MI:0914”(association)	0.640
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	0.640
YBX1	FBXO33	psi-mi:“MI:0915”(physical association)	0.640
FBXO33	YBX1	psi-mi:“MI:0915”(physical association)	0.640
FBXO33	CUL1	psi-mi:“MI:0915”(physical association)	0.560
VTN	HAT1	psi-mi:“MI:0914”(association)	0.530
FBXO33	RBX1	psi-mi:“MI:0915”(physical association)	0.400
IPO5	FBXO33	psi-mi:“MI:0915”(physical association)	0.400
FBXO33	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
HSPA9	FBXO33	psi-mi:“MI:0915”(physical association)	0.400
DDX3X	FBXO33	psi-mi:“MI:0915”(physical association)	0.400
FBXO33	C1QBP	psi-mi:“MI:0915”(physical association)	0.400
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
KLHL2	DCTN6	psi-mi:“MI:0914”(association)	0.350
VTN	HAT1	psi-mi:“MI:0914”(association)	0.350
STYX	PAK4	psi-mi:“MI:0914”(association)	0.350
YBX2		psi-mi:“MI:0914”(association)	0.350
SKP1	BHLHE40	psi-mi:“MI:0914”(association)	0.350
CHCHD2	RECQL4	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350

BioGRID (34): FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-MS), FBXO33 (PCA), FBXO33 (Affinity Capture-MS), FBXO33 (Affinity Capture-Western), ATXN3 (Affinity Capture-Western), FBXO33 (Affinity Capture-MS), NHP2 (Affinity Capture-MS), MRPL21 (Affinity Capture-MS), MRPL17 (Affinity Capture-MS), YBX1 (Affinity Capture-MS)

ESM2 similar proteins: A4IFQ0, O94955, Q08BT5, Q13769, Q14161, Q1A730, Q1JQA1, Q1RMS8, Q1RMZ1, Q2KHT6, Q3T0J1, Q3ZK22, Q4R372, Q5RAQ5, Q5RCQ0, Q5RFL7, Q5T9G4, Q5XI52, Q5XII8, Q5ZJ87, Q5ZJK1, Q60769, Q641X7, Q66H91, Q68FX7, Q6ZPY2, Q7Z6J8, Q7Z6M2, Q8BKT7, Q8BXK4, Q8C0Q9, Q8CHQ0, Q8IWR0, Q8K2I9, Q8N5C7, Q8NFG4, Q8NFZ0, Q8TCJ0, Q8VE08, Q91W96

Diamond homologs: A8QGZ7, B3FL73, Q32PG9, Q3ZBA7, Q5NBU5, Q66H10, Q7Z6M2, Q8BFZ4, Q8C4V4, Q8VE08, Q9EPX5, Q9NXK8, Q9UKT6, Q9UKT7, Q8N4B4

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
FBXO33	“down-regulates quantity by destabilization”	YBX1	binding
FBXO33	“up-regulates activity”	SCF-betaTRCP	binding
FBXO33	“down-regulates quantity by destabilization”	EIF3F	polyubiquitination
FBXO33	“up-regulates activity”	“Cullin 1-RBX1-Skp1”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

98 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

661 predictions. Top by Δscore:

Variant	Effect	Δscore
14:39399783:GTAAC:G	acceptor_gain	1.0000
14:39399784:TAAC:T	acceptor_gain	1.0000
14:39399785:AAC:A	acceptor_gain	1.0000
14:39399785:AACC:A	acceptor_loss	1.0000
14:39399786:AC:A	acceptor_gain	1.0000
14:39399786:ACCT:A	acceptor_loss	1.0000
14:39399787:CC:C	acceptor_gain	1.0000
14:39399787:CCT:C	acceptor_loss	1.0000
14:39399788:C:CC	acceptor_gain	1.0000
14:39399795:A:AC	acceptor_gain	1.0000
14:39399795:A:C	acceptor_gain	1.0000
14:39402394:AACTT:A	donor_loss	1.0000
14:39402395:ACTT:A	donor_loss	1.0000
14:39402396:CTTAC:C	donor_loss	1.0000
14:39402397:TTACT:T	donor_loss	1.0000
14:39402398:TACTG:T	donor_loss	1.0000
14:39402399:A:AC	donor_gain	1.0000
14:39402400:C:CA	donor_gain	1.0000
14:39402400:CT:C	donor_gain	1.0000
14:39402400:CTG:C	donor_gain	1.0000
14:39402400:CTGT:C	donor_gain	1.0000
14:39431559:CCTA:C	donor_loss	1.0000
14:39431560:CTAC:C	donor_loss	1.0000
14:39431563:C:CT	donor_loss	1.0000
14:39399788:C:T	acceptor_gain	0.9900
14:39399789:T:A	acceptor_loss	0.9900
14:39401170:ACCT:A	donor_loss	0.9900
14:39401171:CCTA:C	donor_loss	0.9900
14:39401172:CTA:C	donor_loss	0.9900
14:39401174:A:AC	donor_gain	0.9900

AlphaMissense

3598 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:39399763:A:G	L474P	1.000
14:39399611:A:G	W525R	0.999
14:39399611:A:T	W525R	0.999
14:39399646:A:G	L513P	0.999
14:39399702:G:C	S494R	0.999
14:39399702:G:T	S494R	0.999
14:39399704:T:G	S494R	0.999
14:39399715:A:T	V490D	0.999
14:39399751:G:T	A478D	0.999
14:39399609:C:A	W525C	0.998
14:39399609:C:G	W525C	0.998
14:39399700:A:T	I495N	0.998
14:39399721:A:G	L488P	0.998
14:39399730:A:G	L485P	0.998
14:39399757:G:T	A476D	0.998
14:39399763:A:T	L474H	0.998
14:39399787:C:A	G466V	0.998
14:39399787:C:T	G466D	0.998
14:39401176:C:G	G466R	0.998
14:39401212:A:G	W454R	0.998
14:39401212:A:T	W454R	0.998
14:39401223:A:T	V450D	0.998
14:39401233:C:G	D447H	0.998
14:39401494:A:G	W360R	0.998
14:39401494:A:T	W360R	0.998
14:39401640:A:G	L311P	0.998
14:39401724:A:G	L283P	0.998
14:39431782:G:C	F127L	0.998
14:39431782:G:T	F127L	0.998
14:39431784:A:G	F127L	0.998

dbSNP variants (sampled 300 via entrez): RS1000025546 (14:39433317 C>G,T), RS1000152701 (14:39410085 C>A,T), RS1000175848 (14:39403411 C>A,T), RS1000231087 (14:39397469 T>C), RS1000238273 (14:39407046 G>C), RS1000274672 (14:39428455 C>G,T), RS1000345446 (14:39397598 G>A,T), RS1000391593 (14:39413184 C>T), RS1000435673 (14:39430554 G>A,C), RS1000507376 (14:39403152 GTTAAT>G), RS1000568417 (14:39430782 T>C), RS1000619542 (14:39424675 G>A), RS1000639076 (14:39419744 A>G), RS1000695159 (14:39406801 G>A), RS1000870074 (14:39414208 AG>A)

Disease associations

OMIM: gene MIM:609103 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003457_4	Soluble receptor for advanced glycation end-product levels	5.000000e-06
GCST006616_5	Uterine fibroid number (single vs multiple)	7.000000e-07
GCST006628_53	Systolic blood pressure	2.000000e-11
GCST007326_71	Number of sexual partners	1.000000e-08
GCST009391_1692	Metabolite levels	9.000000e-06
GCST010151_22	Carotid intima media thickness x smoking interaction	2.000000e-06
GCST010988_484	Adult body size	4.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007819	advanced glycation end-product measurement
EFO:0009410	uterine fibroid measurement
EFO:0006335	systolic blood pressure
EFO:0010343	cholesteryl ester 18:0 measurement
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	increases expression, increases methylation	3
(+)-JQ1 compound	increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Valproic Acid	increases expression, affects expression, decreases methylation	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation	1
Cadmium	increases abundance, increases expression	1
Ozone	increases abundance, affects expression	1
Potassium Chloride	decreases response to substance, increases expression	1
Dronabinol	decreases response to substance, increases expression	1
Thiram	increases expression	1
Urethane	increases expression	1
Vincristine	decreases expression	1
Zinc	affects cotreatment, increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.