O95967 (FBLN4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
EGF-containing fibulin-like extracellular matrix protein 2

Alternative name(s):
Fibulin-4
Short name=FIBL-4
Protein UPH1

Gene names

Name:	EFEMP2
Synonyms:	FBLN4
ORF Names:	UNQ200/PRO226

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	443 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Subcellular location	Secreted.
Involvement in disease	Cutis laxa, autosomal recessive, 1B (ARCL1B) [MIM:614437]: A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. ARCL1B features include emphysema, lethal pulmonary artery occlusion, aortic aneurysm, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.10 Ref.11 Ref.12
Sequence similarities	Belongs to the fibulin family. Contains 6 EGF-like domains.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	EGF-like domain Repeat Signal
Ligand	Calcium
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	blood coagulation Inferred from electronic annotation. Source: InterPro extracellular matrix organization Traceable author statement. Source: Reactome
Cellular_component	basement membrane Traceable author statement Ref.1. Source: ProtInc membrane Inferred from electronic annotation. Source: InterPro
Molecular_function	calcium ion binding Inferred from electronic annotation. Source: InterPro extracellular matrix structural constituent Traceable author statement Ref.1. Source: ProtInc transmembrane signaling receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ATN1	P54259	3	EBI-743414,EBI-945980
ELN	P15502	5	EBI-743414,EBI-1222108
FBLN5	Q9UBX5	3	EBI-743414,EBI-947897
FBN1	P35555	3	EBI-743414,EBI-2505934
Hoxa1	P09022	3	EBI-743414,EBI-3957603	From a different organism.
LOX	P28300	4	EBI-743414,EBI-3893481
RHOXF2	Q9BQY4	2	EBI-743414,EBI-372094

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 25

25

Potential

Chain

26 – 443

418

EGF-containing fibulin-like extracellular matrix protein 2

PRO_0000007575

Regions

Domain

36 – 81

46

EGF-like 1; atypical

Domain

123 – 163

41

EGF-like 2; calcium-binding Potential

Domain

164 – 202

39

EGF-like 3; calcium-binding Potential

Domain

203 – 242

40

EGF-like 4; calcium-binding Potential

Domain

243 – 282

40

EGF-like 5; calcium-binding Potential

Domain

283 – 328

46

EGF-like 6; calcium-binding Potential

Amino acid modifications

Glycosylation

198

1

N-linked (GlcNAc...) Potential

Glycosylation

394

1

N-linked (GlcNAc...) Potential

Disulfide bond

58 ↔ 121

Ref.9

Disulfide bond

65 ↔ 80

Ref.9

Disulfide bond

71 ↔ 109

Ref.9

Disulfide bond

127 ↔ 140

By similarity

Disulfide bond

134 ↔ 149

By similarity

Disulfide bond

151 ↔ 162

By similarity

Disulfide bond

168 ↔ 177

By similarity

Disulfide bond

173 ↔ 186

By similarity

Disulfide bond

188 ↔ 201

By similarity

Disulfide bond

207 ↔ 217

By similarity

Disulfide bond

213 ↔ 226

By similarity

Disulfide bond

228 ↔ 241

By similarity

Disulfide bond

247 ↔ 258

By similarity

Disulfide bond

254 ↔ 267

By similarity

Disulfide bond

269 ↔ 281

By similarity

Disulfide bond

287 ↔ 300

By similarity

Disulfide bond

294 ↔ 309

By similarity

Disulfide bond

315 ↔ 327

By similarity

Natural variations

Natural variant

57

1

E → K in ARCL1B. Ref.10

VAR_027019

Natural variant

259

1

I → V. Ref.1 Ref.2 Ref.3 Ref.4 Ref.5 Ref.6 Ref.8
Corresponds to variant rs601314 [ dbSNP | Ensembl ].

VAR_027020

Natural variant

267

1

C → Y in ARCL1B. Ref.12

VAR_067069

Natural variant

279

1

R → C in ARCL1B. Ref.11

VAR_067070

Experimental info

Sequence conflict

5

1

A → T in CAA10791. Ref.1

Sequence conflict

44 – 51

8

EWDPDSQH → TQTAN in AAC62108. Ref.2

Sequence conflict

46

1

D → G in BAF84768. Ref.4

Sequence conflict

96

1

P → L in BAG50843. Ref.4

Sequence conflict

103 – 111

9

AQHPNPCPP → VNTQPLPT in AAC62108. Ref.2

Sequence conflict

294

1

C → W in AAC62108. Ref.2

Sequence conflict

354 – 356

3

RSV → AER in AAC62108. Ref.2

Sequence conflict

355

1

S → R in AAF65188. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

443

Helix Strand Turn

Details...

Beta strand

68 – 73

6

Beta strand

78 – 82

5

Beta strand

113 – 116

4

Sequences

	Sequence		Length	Mass (Da)
	O95967 [UniParc]. Last modified March 20, 2007. Version 3. Checksum: 9315CFBBAA0FD3A7	FASTA	443	49,405
	10 20 30 40 50 60 MLPCASCLPG SLLLWALLLL LLGSASPQDS EEPDSYTECT DGYEWDPDSQ HCRDVNECLT 70 80 90 100 110 120 IPEACKGEMK CINHYGGYLC LPRSAAVIND LHGEGPPPPV PPAQHPNPCP PGYEPDDQDS 130 140 150 160 170 180 CVDVDECAQA LHDCRPSQDC HNLPGSYQCT CPDGYRKIGP ECVDIDECRY RYCQHRCVNL 190 200 210 220 230 240 PGSFRCQCEP GFQLGPNNRS CVDVNECDMG APCEQRCFNS YGTFLCRCHQ GYELHRDGFS 250 260 270 280 290 300 CSDIDECSYS SYLCQYRCIN EPGRFSCHCP QGYQLLATRL CQDIDECESG AHQCSEAQTC 310 320 330 340 350 360 VNFHGGYRCV DTNRCVEPYI QVSENRCLCP ASNPLCREQP SSIVHRYMTI TSERSVPADV 370 380 390 400 410 420 FQIQATSVYP GAYNAFQIRA GNSQGDFYIR QINNVSAMLV LARPVTGPRE YVLDLEMVTM 430 440 NSLMSYRASS VLRLTVFVGA YTF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4." Giltay R., Timpl R., Kostka G. Matrix Biol. 18:469-480(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259. Tissue: Melanoma.
[2]	Zemel R., Shaul Y. Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259.
[3]	"Isolation of a paralog of the Doyne honeycomb retinal dystrophy gene from the multiple retinopathy critical region on 11q13." Katsanis N., Venable S., Smith J.R., Lupski J.R. Hum. Genet. 106:66-72(2000) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT VAL-259.
[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], VARIANT VAL-259. Tissue: Embryo and Synovium.
[5]	"The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment." Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J., Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P., Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E. , Heldens S., Huang A., Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D., Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L., Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C., Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J., Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M. Genome Res. 13:2265-2270(2003) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259.
[6]	"Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries." Otsuki T., Ota T., Nishikawa T., Hayashi K., Suzuki Y., Yamamoto J., Wakamatsu A., Kimura K., Sakamoto K., Hatano N., Kawai Y., Ishii S., Saito K., Kojima S., Sugiyama T., Ono T., Okano K., Yoshikawa Y. , Aotsuka S., Sasaki N., Hattori A., Okumura K., Nagai K., Sugano S., Isogai T. DNA Res. 12:117-126(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT VAL-259. Tissue: Placenta.
[7]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. , Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C., Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A., Hattori M., Rogers J., Lander E.S., Sakaki Y. Nature 440:497-500(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"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], VARIANT VAL-259. Tissue: Brain.
[9]	"Solution NMR structure of the EGF-like 1 domain of human fibulin-4." Northeast structural genomics consortium (NESG) Submitted (JUL-2009) to the PDB data bank Cited for: STRUCTURE BY NMR OF 54-123, DISULFIDE BONDS.
[10]	"Fibulin-4: a novel gene for an autosomal recessive cutis laxa syndrome." Hucthagowder V., Sausgruber N., Kim K.H., Angle B., Marmorstein L.Y., Urban Z. Am. J. Hum. Genet. 78:1075-1080(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARCL1B LYS-57.
[11]	"Compound heterozygous mutations in fibulin-4 causing neonatal lethal pulmonary artery occlusion, aortic aneurysm, arachnodactyly, and mild cutis laxa." Dasouki M., Markova D., Garola R., Sasaki T., Charbonneau N.L., Sakai L.Y., Chu M.L. Am. J. Med. Genet. A 143:2635-2641(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARCL1B CYS-279.
[12]	"Lethal cutis laxa with contractural arachnodactyly, overgrowth and soft tissue bleeding due to a novel homozygous fibulin-4 gene mutation." Hoyer J., Kraus C., Hammersen G., Geppert J.P., Rauch A. Clin. Genet. 76:276-281(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARCL1B TYR-267.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AJ132819 mRNA. Translation: CAA10791.2.
AF093119 mRNA. Translation: AAC62108.1.
AF109121 mRNA. Translation: AAF65188.1.
AK000980 mRNA. Translation: BAG50843.1.
AK292079 mRNA. Translation: BAF84768.1.
AY358899 mRNA. Translation: AAQ89258.1.
AK075453 mRNA. Translation: BAG52143.1.
AP001201 Genomic DNA. No translation available.
BC010456 mRNA. Translation: AAH10456.1.

IPI

IPI00296058.

RefSeq

NP_058634.4. NM_016938.4.

UniGene

Hs.731454.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KL7	NMR	-	A	54-123	[»]

ProteinModelPortal

O95967.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34518N.

IntAct

O95967. 43 interactions.

MINT

MINT-1439082.

STRING

9606.ENSP00000309953.

PTM databases

PhosphoSite

O95967.

Proteomic databases

PaxDb

O95967.

PRIDE

O95967.

Protocols and materials databases

DNASU

30008.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000307998; ENSP00000309953; ENSG00000172638.
ENST00000531972; ENSP00000435295; ENSG00000172638.

GeneID

30008.

KEGG

hsa:30008.

UCSC

uc001ofy.4. human.

Organism-specific databases

CTD

30008.

GeneCards

GC11M065633.

HGNC

HGNC:3219. EFEMP2.

HPA

HPA023270.

MIM

604633. gene.
614437. phenotype.

neXtProt

NX_O95967.

Orphanet

90349. Autosomal recessive cutis laxa type 1.
314718. Lethal arteriopathy syndrome due to FBLN4 deficiency.

PharmGKB

PA27653.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG254862.

HOGENOM

HOG000234337.

HOVERGEN

HBG051560.

InParanoid

O95967.

OMA

QRCYNTY.

OrthoDB

EOG4K6G47.

PhylomeDB

O95967.

Enzyme and pathway databases

Reactome

REACT_118779. Extracellular matrix organization.

Gene expression databases

ArrayExpress

O95967.

Bgee

O95967.

CleanEx

HS_EFEMP2.

Genevestigator

O95967.

GermOnline

ENSG00000172638. Homo sapiens.

Family and domain databases

InterPro

IPR026823. cEGF.
IPR026824. Efemp1/Efemp2.
IPR000742. EG-like_dom.
IPR001881. EGF-like_Ca-bd.
IPR013032. EGF-like_CS.
IPR000152. EGF-type_Asp/Asn_hydroxyl_site.
IPR018097. EGF_Ca-bd_CS.
IPR001491. Thrombomodulin.
[Graphical view]

PANTHER

PTHR24048:SF2. PTHR24048:SF2. 1 hit.

Pfam

PF12662. cEGF. 2 hits.
PF07645. EGF_CA. 3 hits.
[Graphical view]

PRINTS

PR00907. THRMBOMODULN.

SMART

SM00181. EGF. 1 hit.
SM00179. EGF_CA. 4 hits.
[Graphical view]

PROSITE

PS00010. ASX_HYDROXYL. 4 hits.
PS00022. EGF_1. False negative.
PS01186. EGF_2. 4 hits.
PS50026. EGF_3. 4 hits.
PS01187. EGF_CA. 6 hits.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

O95967.

GenomeRNAi

30008.

NextBio

52820.

SOURCE

Search...

Entry information

Entry name

FBLN4_HUMAN

Accession

Primary (citable) accession number: O95967
Secondary accession number(s): A8K7R4 , B3KM31, B3KQT1, O75967

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 2000
Last sequence update:	March 20, 2007
Last modified:	May 29, 2013
This is version 139 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.