Q9UKC9 (FBXL2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
F-box/LRR-repeat protein 2

Alternative name(s):
F-box and leucine-rich repeat protein 2
F-box protein FBL2/FBL3

Gene names

Name:	FBXL2
Synonyms:	FBL2, FBL3

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	423 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Calcium-activated substrate recognition component of a SCF (SKP1-cullin-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Unlike many F-box proteins, FBXL2 doesn't seem to target phosphodegron within its substrates but rather calmodulin-binding motifs. Targets PCYT1A for its monoubiquitination and degradation, this is antagonized by calmodulin By similarity. Targets the cyclins CCND2 and CCND3 for polyubiquitination and degradation, leading to cell-cycle arrest in G0, also antagonized by calmodulin. Binds to hepatitis C virus non-structural protein 5A (NS5A) in a reaction crucial for hepatitis C virus RNA replication. Ref.9 Ref.10 Ref.11
Subunit structure	Interacts with SKP1. Interacts with PCYT1A. Part of a SCF (SKP1-cullin-F-box) protein ligase complex By similarity. Interacts (via CAAX motif) with hepatitis C virus non-structural protein 5A (NS5A). May also interact, but less efficiently, with hepatitis C virus non-structural protein 5B (NS5B). Interacts with CCND2 and CCND3. Ref.2 Ref.9 Ref.10 Ref.11
Subcellular location	Membrane; Lipid-anchor Ref.9.
Tissue specificity	Expressed in brain, heart, kidney, liver, lung, pancreas and placenta. Ref.2
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.
Sequence similarities	Contains 1 F-box domain. Contains 13 LRR (leucine-rich) repeats.
Sequence caution	The sequence AAF03128.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Host-virus interaction Ubl conjugation pathway
Cellular component	Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Leucine-rich repeat Repeat
Ligand	Calcium Calmodulin-binding
PTM	Lipoprotein Prenylation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	protein monoubiquitination Inferred from electronic annotation. Source: Compara proteolysis Traceable author statement Ref.1. Source: ProtInc ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: Compara virus-host interaction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasm Traceable author statement PubMed 10508920. Source: ProtInc membrane Inferred from direct assay Ref.9. Source: UniProtKB
Molecular_function	ubiquitin-protein ligase activity Traceable author statement Ref.2. Source: ProtInc
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: 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.

Isoform 2 (identifier: Q9UKC9-2)

The sequence of this isoform differs from the canonical sequence as follows:
     132-199: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 423	423	F-box/LRR-repeat protein 2		PRO_0000119840
Regions
	Domain	9 – 55	47	F-box
	Repeat	61 – 87	27	LRR 1
	Repeat	88 – 113	26	LRR 2
	Repeat	114 – 139	26	LRR 3
	Repeat	140 – 165	26	LRR 4
	Repeat	166 – 191	26	LRR 5
	Repeat	192 – 217	26	LRR 6
	Repeat	218 – 243	26	LRR 7
	Repeat	244 – 269	26	LRR 8
	Repeat	270 – 295	26	LRR 9
	Repeat	296 – 321	26	LRR 10
	Repeat	322 – 350	29	LRR 11
	Repeat	351 – 375	25	LRR 12
	Repeat	376 – 401	26	LRR 13
	Region	80 – 90	11	Interaction with Calmodulin By similarity
	Motif	420 – 423	4	CAAX motif
Amino acid modifications
	Lipidation	420	1	S-geranylgeranyl cysteine Probable
Natural variations
	Alternative sequence	132 – 199	68	Missing in isoform 2.		VSP_044600
	Natural variant	226	1	V → M in a colorectal cancer sample; somatic mutation. Ref.12		VAR_036071
Experimental info
	Mutagenesis	420	1	C → S: Loss of geranylgeranylation and association to membranes. Ref.9
	Sequence conflict	62	1	T → I in AAF04510. Ref.1
	Sequence conflict	62	1	T → I in AAF03128. Ref.2
	Sequence conflict	62	1	T → I in CAG33402. Ref.5
	Sequence conflict	77	1	G → V in AAF04510. Ref.1
	Sequence conflict	81	1	R → K in BAA91691. Ref.4
	Sequence conflict	108	1	H → Q in BAG61062. Ref.4
	Sequence conflict	174	1	I → W in CAB43222. Ref.8
	Sequence conflict	320	1	S → P in CAB43222. Ref.8
	Sequence conflict	342	1	R → G in CAG33402. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified April 17, 2007. Version 3. Checksum: 61938E434618BA3D	FASTA	423	47,062
	10 20 30 40 50 60 MVFSNNDEGL INKKLPKELL LRIFSFLDIV TLCRCAQISK AWNILALDGS NWQRIDLFNF 70 80 90 100 110 120 QTDVEGRVVE NISKRCGGFL RKLSLRGCIG VGDSSLKTFA QNCRNIEHLN LNGCTKITDS 130 140 150 160 170 180 TCYSLSRFCS KLKHLDLTSC VSITNSSLKG ISEGCRNLEY LNLSWCDQIT KDGIEALVRG 190 200 210 220 230 240 CRGLKALLLR GCTQLEDEAL KHIQNYCHEL VSLNLQSCSR ITDEGVVQIC RGCHRLQALC 250 260 270 280 290 300 LSGCSNLTDA SLTALGLNCP RLQILEAARC SHLTDAGFTL LARNCHELEK MDLEECILIT 310 320 330 340 350 360 DSTLIQLSIH CPKLQALSLS HCELITDDGI LHLSNSTCGH ERLRVLELDN CLLITDVALE 370 380 390 400 410 420 HLENCRGLER LELYDCQQVT RAGIKRMRAQ LPHVKVHAYF APVTPPTAVA GSGQRLCRCC VIL
	Isoform 2 [UniParc]. Checksum: F1C3CDED0C7F0131	FASTA	355	39,613
	10 20 30 40 50 60 MVFSNNDEGL INKKLPKELL LRIFSFLDIV TLCRCAQISK AWNILALDGS NWQRIDLFNF 70 80 90 100 110 120 QTDVEGRVVE NISKRCGGFL RKLSLRGCIG VGDSSLKTFA QNCRNIEHLN LNGCTKITDS 130 140 150 160 170 180 TCYSLSRFCS KLKHIQNYCH ELVSLNLQSC SRITDEGVVQ ICRGCHRLQA LCLSGCSNLT 190 200 210 220 230 240 DASLTALGLN CPRLQILEAA RCSHLTDAGF TLLARNCHEL EKMDLEECIL ITDSTLIQLS 250 260 270 280 290 300 IHCPKLQALS LSHCELITDD GILHLSNSTC GHERLRVLEL DNCLLITDVA LEHLENCRGL 310 320 330 340 350 ERLELYDCQQ VTRAGIKRMR AQLPHVKVHA YFAPVTPPTA VAGSGQRLCR CCVIL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a family of human F-box proteins." Cenciarelli C., Chiaur D.S., Guardavaccaro D., Parks W., Vidal M., Pagano M. Curr. Biol. 9:1177-1179(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[2]	"A family of mammalian F-box proteins." Winston J.T., Koepp D.M., Zhu C., Elledge S.J., Harper J.W. Curr. Biol. 9:1180-1182(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH SKP1, TISSUE SPECIFICITY.
[3]	"cDNA cloning and expression analysis of new members of the mammalian F-box protein family." Ilyin G.P., Rialland M., Pigeon C., Guguen-Guillouzo C. Genomics 67:40-47(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
[5]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]	"The DNA sequence, annotation and analysis of human chromosome 3." Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J. , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A. Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[7]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Brain.
[8]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 174-423 (ISOFORM 1). Tissue: Brain.
[9]	"Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication." Wang C., Gale M. Jr., Keller B.C., Huang H., Brown M.S., Goldstein J.L., Ye J. Mol. Cell 18:425-434(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH HEPATITIS C VIRUS NS5A, ISOPRENYLATION AT CYS-420, MUTAGENESIS OF CYS-420, SUBCELLULAR LOCATION.
[10]	"F-box protein FBXL2 targets cyclin D2 for ubiquitination and degradation to inhibit leukemic cell proliferation." Chen B.B., Glasser J.R., Coon T.A., Zou C., Miller H.L., Fenton M., McDyer J.F., Boyiadzis M., Mallampalli R.K. Blood 119:3132-3141(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH CCND2.
[11]	"F-box protein FBXL2 exerts human lung tumor suppressor-like activity by ubiquitin-mediated degradation of cyclin D3 resulting in cell cycle arrest." Chen B.B., Glasser J.R., Coon T.A., Mallampalli R.K. Oncogene 31:2566-2579(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH CCND3.
[12]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] MET-226.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF174589 mRNA. Translation: AAF04510.1. AF176518 mRNA. Translation: AAF03128.1. Different initiation. AF186273 mRNA. Translation: AAD56248.1. AK001438 mRNA. Translation: BAA91691.1. AK298967 mRNA. Translation: BAG61062.1. CR457121 mRNA. Translation: CAG33402.1. AC122176 Genomic DNA. No translation available. AC123900 Genomic DNA. No translation available. BC031556 mRNA. Translation: AAH31556.1. AL049953 mRNA. Translation: CAB43222.1.
IPI	IPI00296850. IPI00923623.
PIR	T08680.
RefSeq	NP_001165184.1. NM_001171713.1. NP_036289.3. NM_012157.3.
UniGene	Hs.475872.
3D structure databases
ProteinModelPortal	Q9UKC9.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q9UKC9. 4 interactions.
MINT	MINT-1390736.
STRING	9606.ENSP00000417601.
Polymorphism databases
DMDM	145559475.
Proteomic databases
PaxDb	Q9UKC9.
PRIDE	Q9UKC9.
Protocols and materials databases
DNASU	25827.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000484457; ENSP00000417601; ENSG00000153558. ENST00000507198; ENSP00000426163; ENSG00000153558. ENST00000538892; ENSP00000441228; ENSG00000153558.
GeneID	25827.
KEGG	hsa:25827.
UCSC	uc003cfp.3. human.
Organism-specific databases
CTD	25827.
GeneCards	GC03P033293.
HGNC	HGNC:13598. FBXL2.
MIM	605652. gene.
neXtProt	NX_Q9UKC9.
PharmGKB	PA28021.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG300245.
HOGENOM	HOG000230659.
HOVERGEN	HBG051586.
InParanoid	Q9UKC9.
KO	K10268.
OMA	LTENVFG.
OrthoDB	EOG4KPTB9.
PhylomeDB	Q9UKC9.
Gene expression databases
ArrayExpress	Q9UKC9.
Bgee	Q9UKC9.
CleanEx	HS_FBXL2.
Genevestigator	Q9UKC9.
GermOnline	ENSG00000153558. Homo sapiens.
Family and domain databases
InterPro	IPR001810. F-box_dom_cyclin-like. IPR006553. Leu-rich_rpt_Cys-con_subtyp. [Graphical view]
Pfam	PF00646. F-box. 1 hit. [Graphical view]
SMART	SM00256. FBOX. 1 hit. SM00367. LRR_CC. 2 hits. [Graphical view]
PROSITE	PS50181. FBOX. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChiTaRS	FBXL2. human.
GenomeRNAi	25827.
NextBio	47109.
SOURCE	Search...

Entry information

Entry name

FBXL2_HUMAN

Accession

Primary (citable) accession number: Q9UKC9
Secondary accession number(s): B4DQV0 , E9PD06, Q6IAN3, Q9NVQ8, Q9UK27, Q9UKA5, Q9Y3Y9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 21, 2003
Last sequence update:	April 17, 2007
Last modified:	May 1, 2013
This is version 105 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.