O95633 (FSTL3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Follistatin-related protein 3

Alternative name(s):
Follistatin-like protein 3
Follistatin-related gene protein

Gene names

Name:	FSTL3
Synonyms:	FLRG
ORF Names:	UNQ674/PRO1308

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	263 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)

Function	Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such us activin, BMP2 and MSTN. Inhibits activin A-, activin B-, BMP2- and MSDT-induced cellular signaling; more effective on activin A than on activin B. Involved in bone formation; inhibits osteoclast differentiationc. Involved in hematopoiesis; involved in differentiation of hemopoietic progenitor cells, increases hematopoietic cell adhesion to fibronectin and seems to contribute to the adhesion of hematopoietic precursor cells to the bone marrow stroma. Isoform 2 or the nuclear form is probably involved in transcriptional regulation via interaction with MLLT10. Ref.8 Ref.11 Ref.12 Ref.14 Ref.15 Ref.16
Subunit structure	Interacts with INHBA and INHBB. Interacts with FN1. Interacts with ADAM12. Isoform 2 interacts with MLLT10; the interaction enhances MLLT10 in vitro transcriptional activity and self-association. Interacts with MSTN. Ref.9 Ref.12 Ref.14 Ref.15 Ref.16
Subcellular location	Isoform 1: Secreted Ref.7 Ref.10 Ref.13. Isoform 2: Nucleus. Note: Although alternative initiation has been demonstrated and resulted in different localization, the major source of nuclear FSTL3 appears not to depend on translation initation at Met-27 according to (Ref.13). Ref.7 Ref.10 Ref.13
Tissue specificity	Expressed in a wide range of tissues. Ref.7
Involvement in disease	Note=A chromosomal aberration involving FSTL3 is found in a case of B-cell chronic lymphocytic leukemia. Translocation t(11;19)(q13;p13) with CCDN1.
Sequence similarities	Contains 2 follistatin-like domains. Contains 2 Kazal-like domains. Contains 1 TB (TGF-beta binding) domain.

Ontologies

Keywords
Biological process	Osteogenesis Transcription Transcription regulation
Cellular component	Nucleus Secreted
Coding sequence diversity	Alternative initiation Chromosomal rearrangement
Disease	Proto-oncogene
Domain	Repeat Signal
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	hemopoietic progenitor cell differentiation Inferred from direct assay Ref.11. Source: UniProtKB negative regulation of BMP signaling pathway Inferred from direct assay Ref.16. Source: UniProtKB negative regulation of activin receptor signaling pathway Inferred from direct assay Ref.8Ref.9. Source: UniProtKB negative regulation of osteoclast differentiation Inferred from direct assay Ref.12. Source: UniProtKB ossification Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of cell-cell adhesion Inferred from direct assay Ref.14. Source: UniProtKB positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay Ref.15. Source: UniProtKB transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	extracellular space Inferred from direct assay Ref.13. Source: UniProtKB nucleus Inferred from direct assay Ref.13. Source: UniProtKB
Molecular function	activin binding Inferred from physical interaction Ref.9. Source: UniProtKB fibronectin binding Inferred from physical interaction Ref.14. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ADAM12	O43184-2	4	EBI-2625790,EBI-2625865

Alternative products

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

Isoform 1 (identifier: O95633-1)

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: O95633-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-26: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

26

Ref.6

Chain

27 – 263

237

Follistatin-related protein 3

PRO_0000010115

Regions

Domain

36 – 107

72

TB

Domain

99 – 119

21

Follistatin-like 1

Domain

113 – 169

57

Kazal-like 1

Domain

170 – 193

24

Follistatin-like 2

Domain

189 – 245

57

Kazal-like 2

Amino acid modifications

Glycosylation

73

1

N-linked (GlcNAc...) Potential

Glycosylation

215

1

N-linked (GlcNAc...) Ref.17

Disulfide bond

38 ↔ 61

Ref.17

Disulfide bond

48 ↔ 92

Ref.17

Disulfide bond

62 ↔ 95

Ref.17

Disulfide bond

99 ↔ 110

Ref.17

Disulfide bond

104 ↔ 119

Ref.17

Disulfide bond

121 ↔ 153

Ref.17

Disulfide bond

125 ↔ 146

Ref.17

Disulfide bond

135 ↔ 167

Ref.17

Disulfide bond

171 ↔ 182

Ref.17

Disulfide bond

176 ↔ 192

Ref.17

Disulfide bond

195 ↔ 229

Ref.17

Disulfide bond

200 ↔ 222

Ref.17

Disulfide bond

211 ↔ 243

Ref.17

Natural variations

Alternative sequence

1 – 26

26

Missing in isoform 2.

VSP_038553

Experimental info

Mutagenesis

27

1

M → A: Nuclear localization. Ref.13

Secondary structure

1

.

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.

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.

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.

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.

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263

Helix Strand Turn

Details...

Beta strand

38 – 41

4

Beta strand

48 – 55

8

Helix

58 – 61

4

Beta strand

69 – 71

3

Helix

80 – 83

4

Beta strand

93 – 95

3

Beta strand

109 – 111

3

Beta strand

118 – 120

3

Beta strand

142 – 144

3

Helix

145 – 153

9

Beta strand

169 – 171

3

Beta strand

181 – 184

4

Beta strand

190 – 193

4

Beta strand

218 – 220

3

Helix

221 – 230

10

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified May 1, 1999. Version 1. Checksum: 6A9AB86ADD4FD09C	FASTA	263	27,663
	10 20 30 40 50 60 MRPGAPGPLW PLPWGALAWA VGFVSSMGSG NPAPGGVCWL QQGQEATCSL VLQTDVTRAE 70 80 90 100 110 120 CCASGNIDTA WSNLTHPGNK INLLGFLGLV HCLPCKDSCD GVECGPGKAC RMLGGRPRCE 130 140 150 160 170 180 CAPDCSGLPA RLQVCGSDGA TYRDECELRA ARCRGHPDLS VMYRGRCRKS CEHVVCPRPQ 190 200 210 220 230 240 SCVVDQTGSA HCVVCRAAPC PVPSSPGQEL CGNNNVTYIS SCHMRQATCF LGRSIGVRHA 250 260 GSCAGTPEEP PGGESAEEEE NFV
	Isoform 2 [UniParc]. Checksum: 499A1E50592DDFE4	FASTA	237	24,960
	10 20 30 40 50 60 MGSGNPAPGG VCWLQQGQEA TCSLVLQTDV TRAECCASGN IDTAWSNLTH PGNKINLLGF 70 80 90 100 110 120 LGLVHCLPCK DSCDGVECGP GKACRMLGGR PRCECAPDCS GLPARLQVCG SDGATYRDEC 130 140 150 160 170 180 ELRAARCRGH PDLSVMYRGR CRKSCEHVVC PRPQSCVVDQ TGSAHCVVCR AAPCPVPSSP 190 200 210 220 230 GQELCGNNNV TYISSCHMRQ ATCFLGRSIG VRHAGSCAGT PEEPPGGESA EEEENFV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"FLRG (follistatin-related gene), a new target of chromosomal rearrangement in malignant blood disorders." Hayette S., Gadoux M., Martel S., Bertrand S., Tigaud I., Magaud J.-P., Rimokh R. Oncogene 16:2949-2954(1998) [PubMed: 9671416] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], CHROMOSOMAL TRANSLOCATION. Tissue: Placenta.
[2]	"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: 12975309] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"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: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta.
[6]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed: 15340161] [Abstract] Cited for: PROTEIN SEQUENCE OF 27-41.
[7]	"Human follistatin-related protein: a structural homologue of follistatin with nuclear localization." Tortoriello D.V., Sidis Y., Holtzman D.A., Holmes W.E., Schneyer A.L. Endocrinology 142:3426-3434(2001) [PubMed: 11459787] [Abstract] Cited for: TISSUE SPECIFICITY, SUBCELLULAR LOCATION.
[8]	"Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function." Bartholin L., Maguer-Satta V., Hayette S., Martel S., Gadoux M., Corbo L., Magaud J.P., Rimokh R. Oncogene 21:2227-2235(2002) [PubMed: 11948405] [Abstract] Cited for: FUNCTION.
[9]	"Differential binding and neutralization of activins A and B by follistatin and follistatin like-3 (FSTL-3/FSRP/FLRG)." Schneyer A., Schoen A., Quigg A., Sidis Y. Endocrinology 144:1671-1674(2003) [PubMed: 12697670] [Abstract] Cited for: INTERACTION WITH INHBA AND INHBB.
[10]	"Follistatin-related gene (FLRG) expression in human endometrium: sex steroid hormones regulate the expression of FLRG in cultured human endometrial stromal cells." Wang H.Q., Takebayashi K., Tsuchida K., Nishimura M., Noda Y. J. Clin. Endocrinol. Metab. 88:4432-4439(2003) [PubMed: 12970321] [Abstract] Cited for: SUBCELLULAR LOCATION.
[11]	"FLRG, member of the follistatin family, a new player in hematopoiesis." Maguer-Satta V., Rimokh R. Mol. Cell. Endocrinol. 225:109-118(2004) [PubMed: 15451575] [Abstract] Cited for: FUNCTION IN HEMATOPOIESIS.
[12]	"FLRG, a new ADAM12-associated protein, modulates osteoclast differentiation." Bartholin L., Destaing O., Forissier S., Martel S., Maguer-Satta V., Jurdic P., Rimokh R. Biol. Cell 97:577-588(2005) [PubMed: 15574124] [Abstract] Cited for: FUNCTION IN OSTEOCLAST DIFFERENTIATION, INTERACTION WITH ADAM8 AND ADAM12.
[13]	"Differential biosynthesis and intracellular transport of follistatin isoforms and follistatin-like-3." Saito S., Sidis Y., Mukherjee A., Xia Y., Schneyer A. Endocrinology 146:5052-5062(2005) [PubMed: 16150905] [Abstract] Cited for: SUBCELLULAR LOCATION, ALTERNATIVE INITIATION, MUTAGENESIS OF MET-27.
[14]	"A novel role for fibronectin type I domain in the regulation of human hematopoietic cell adhesiveness through binding to follistatin domains of FLRG and follistatin." Maguer-Satta V., Forissier S., Bartholin L., Martel S., Jeanpierre S., Bachelard E., Rimokh R. Exp. Cell Res. 312:434-442(2006) [PubMed: 16336961] [Abstract] Cited for: FUNCTION IN HEMATOPOIESIS, INTERACTION WITH FN1.
[15]	"AF10-dependent transcription is enhanced by its interaction with FLRG." Forissier S., Razanajaona D., Ay A.S., Martel S., Bartholin L., Rimokh R. Biol. Cell 99:563-571(2007) [PubMed: 17868029] [Abstract] Cited for: FUNCTION IN TRANSCRIPTION REGULATION, INTERACTION WITH MLLT10.
[16]	"Characterization of follistatin-related gene as a negative regulatory factor for activin family members during mouse heart development." Takehara-Kasamatsu Y., Tsuchida K., Nakatani M., Murakami T., Kurisaki A., Hashimoto O., Ohuchi H., Kurose H., Mori K., Kagami S., Noji S., Sugino H. J. Med. Invest. 54:276-288(2007) [PubMed: 17878677] [Abstract] Cited for: FUNCTION, INTERACTION WITH MSTN.
[17]	"The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity." Stamler R., Keutmann H.T., Sidis Y., Kattamuri C., Schneyer A., Thompson T.B. J. Biol. Chem. 283:32831-32838(2008) [PubMed: 18768470] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.48 ANGSTROMS) OF 27-263 IN COMPLEX WITH INHBA, DISULFIDE BONDS, GLYCOSYLATION AT ASN-215.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U76702 mRNA. Translation: AAC64321.1.
AY358917 mRNA. Translation: AAQ89276.1.
AK291958 mRNA. Translation: BAF84647.1.
CH471242 Genomic DNA. Translation: EAW61165.1.
BC005839 mRNA. Translation: AAH05839.1.

IPI

IPI00025155.
IPI00955041.

RefSeq

NP_005851.1. NM_005860.2.

UniGene

Hs.529038.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KCX	NMR	-	A	97-169	[»]
3B4V	X-ray	2.48	C/D/G/H	27-263	[»]
3SEK	X-ray	2.40	C	36-244	[»]

ProteinModelPortal

O95633.

SMR

O95633. Positions 32-244.

ModBase

Search...

Protein-protein interaction databases

IntAct

O95633. 2 interactions.

STRING

O95633.

Protein family/group databases

MEROPS

I01.968.

Proteomic databases

PeptideAtlas

O95633.

PRIDE

O95633.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000166139; ENSP00000166139; ENSG00000070404.

GeneID

10272.

KEGG

hsa:10272.

UCSC

uc002lpk.1. human.

Organism-specific databases

CTD

10272.

GeneCards

GC19P000676.

H-InvDB

HIX0014560.

HGNC

HGNC:3973. FSTL3.

HPA

CAB024899.

MIM

605343. gene.

neXtProt

NX_O95633.

PharmGKB

PA28390.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG17339.

GeneTree

ENSGT00440000033501.

HOGENOM

HBG445393.

HOVERGEN

HBG051666.

InParanoid

O95633.

OMA

CPRPQSC.

OrthoDB

EOG4TF0M1.

PhylomeDB

O95633.

Gene expression databases

ArrayExpress

O95633.

Bgee

O95633.

CleanEx

HS_FSTL3.

Genevestigator

O95633.

GermOnline

ENSG00000070404. Homo sapiens.

Family and domain databases

InterPro

IPR002212. Fibril-assoc.
IPR003645. Fol_N.
IPR015369. Follistatin/Osteonectin_EGF.
IPR002350. Prot_inh_Kazal.
IPR011497. Prot_Inh_Kazal_2.
IPR017878. TFG_b-bd.
[Graphical view]

Gene3D

G3DSA:3.90.290.10. Fibril-assoc. 1 hit.

Pfam

PF09289. FOLN. 1 hit.
PF07648. Kazal_2. 2 hits.
[Graphical view]

SMART

SM00274. FOLN. 2 hits.
SM00280. KAZAL. 2 hits.
[Graphical view]

PROSITE

PS00282. KAZAL_1. False negative.
PS51465. KAZAL_2. 2 hits.
PS51364. TB. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

NextBio

38914.

PMAP-CutDB

O95633.

SOURCE

Search...

Entry information

Entry name

FSTL3_HUMAN

Accession

Primary (citable) accession number: O95633
Secondary accession number(s): A8K7E3

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 10, 2002
Last sequence update:	May 1, 1999
Last modified:	January 25, 2012
This is version 104 of the entry and version 1 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.