Reviewed, UniProtKB/Swiss-Prot Q16394 (EXT1_HUMAN)

Names and origin

Protein names

Recommended name:
    Exostosin-1
    EC=2.4.1.224
    EC=2.4.1.225
Alternative name(s):
    Glucuronosyl-N-acetylglucosaminyl-proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
    Putative tumor suppressor protein EXT1
    Multiple exostoses protein 1

Gene names

Name:

EXT1

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	746 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor.
Catalytic activity	UDP-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan = UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan. UDP-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan = UDP + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan.
Pathway	Protein modification; protein glycosylation.
Subunit structure	Forms a homo/hetero-oligomeric complex with EXT2.
Subcellular location	Endoplasmic reticulum membrane; Single-pass type II membrane protein. Golgi apparatus membrane; Single-pass type II membrane protein. Note= The EXT1/EXT2 complex is localized in the Golgi apparatus.
Tissue specificity	Ubiquitous.
Involvement in disease	Defects in EXT1 are a cause of hereditary multiple exostoses type 1 (EXT1) [MIM:133700]. EXT is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3 respectively. EXT is a dominantly inherited skeletal disorder primarily affecting endochondral bone during growth. The disease is characterized by formation of numerous cartilage-capped, benign bone tumors (osteocartilaginous exostoses or osteochondromas) that are often accompanied by skeletal deformities and short stature. In a small percentage of cases exostoses have exhibited malignant transformation resulting in an osteosarcoma or chondrosarcoma. Osteochondromas development can also occur as a sporadic event. Defects in EXT1 are the cause of multiple exostoses observed in Langer-Giedon syndrome (LGS) [MIM:150230]; also known as trichorhinophalangeal syndrome type 2 (TRPS2). It is a contiguous gene syndrome due to deletions in chromosome 8q24.1 and resulting in the loss of functional copies of EXT1 and TRPS1. Defects in EXT1 may be a cause of chondrosarcoma [MIM:215300].
Sequence similarities	Belongs to the glycosyltransferase 47 family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Endoplasmic reticulum Golgi apparatus Membrane
Disease	Disease mutation Hereditary multiple exostoses
Domain	Signal-anchor Transmembrane
Molecular function	Anti-oncogene Glycosyltransferase Transferase
PTM	Glycoprotein
Gene Ontology (GO)
Biological process	glycosaminoglycan biosynthetic process Traceable author statement. Source: ProtInc heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW ossification Ref.1 Inferred from mutant phenotype. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc skeletal system development Traceable author statement. Source: ProtInc
Cellular component	Golgi membrane Traceable author statement. Source: UniProtKB integral to endoplasmic reticulum membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular function	N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity Inferred from sequence or structural similarity. Source: UniProtKB glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity Inferred from sequence or structural similarity. Source: UniProtKB heparan sulfate N-acetylglucosaminyltransferase activity Non-traceable author statement. Source: UniProtKB protein heterodimerization activity Inferred from physical interaction. Source: UniProtKB protein homodimerization activity Inferred from direct assay. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CNTF	P26441	1	EBI-1046007,EBI-1050897
OSTF1	Q92882	1	EBI-1046007,EBI-1051152

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 746	746	Exostosin-1		PRO_0000149648
Regions
	Topological domain	1 – 7	7	Cytoplasmic Potential
	Transmembrane	8 – 28	21	Signal-anchor for type II membrane protein Potential
	Topological domain	29 – 746	718	Lumenal Potential
Amino acid modifications
	Glycosylation	89	1	N-linked (GlcNAc...) Potential
	Glycosylation	330	1	N-linked (GlcNAc...) Potential
Natural variations
	Natural variant	27	1	Q → K in EXT1; no loss of activity.		VAR_012815
	Natural variant	164	1	D → H in EXT1; loss of activity.		VAR_012816
	Natural variant	215 – 222	8	MLAKASIS → I in isolated osteochondroma; somatic mutation.		VAR_012818
	Natural variant	215 – 221	7	Missing in EXT1.		VAR_012817
	Natural variant	235 – 239	5	Missing in multiple osteochondromas.		VAR_012819
	Natural variant	280	1	R → G in EXT1; loss of activity.		VAR_002370
	Natural variant	280	1	R → S in EXT1; loss of activity.		VAR_002371
	Natural variant	316	1	N → S in chondrosarcoma; no loss of activity.		VAR_012820
	Natural variant	339	1	G → D in EXT1; loss of activity.		VAR_002372
	Natural variant	340	1	R → C in EXT1; loss of activity; still able to form an oligomeric complex.		VAR_002373
	Natural variant	340	1	R → H in EXT1; loss of activity.		VAR_002374
	Natural variant	340	1	R → L in EXT1; loss of activity.		VAR_002375
	Natural variant	340	1	R → S in EXT1; loss of activity.		VAR_002376
	Natural variant	486	1	A → V in EXT1; no loss of activity.		VAR_012821
	Natural variant	496	1	P → L in EXT1; no loss of activity.		VAR_012822
	Natural variant	627	1	Missing in EXT1; loss of activity.		VAR_002377
Experimental info
	Mutagenesis	27	1	Q → A or P: No effect on heparan-sulfate biosynthesis
	Mutagenesis	27	1	Missing: No effect on heparan-sulfate biosynthesis
	Mutagenesis	164	1	D → E: Abolishes heparan-sulfate biosynthesis
	Mutagenesis	164	1	Missing: Abolishes heparan-sulfate biosynthesis
	Mutagenesis	316	1	N → A: No effect on heparan-sulfate biosynthesis
	Mutagenesis	316	1	Missing: No effect on heparan-sulfate biosynthesis
	Mutagenesis	486	1	A → H: No effect on heparan-sulfate biosynthesis
	Mutagenesis	486	1	Missing: No effect on heparan-sulfate biosynthesis
	Mutagenesis	496	1	P → H: No effect on heparan-sulfate biosynthesis
	Mutagenesis	496	1	Missing: No effect on heparan-sulfate biosynthesis
	Sequence conflict	60 – 61	2	DA → EP Ref.1 Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q16394-1 [UniParc]. Last modified March 27, 2002. Version 2. Checksum: 842CD7E6C1312C1A	FASTA	746	86,255
	10 20 30 40 50 60 MQAKKRYFIL LSAGSCLALL FYFGGLQFRA SRSHSRREEH SGRNGLHHPS PDHFWPRFPD 70 80 90 100 110 120 ALRPFVPWDQ LENEDSSVHI SPRQKRDANS SIYKGKKCRM ESCFDFTLCK KNGFKVYVYP 130 140 150 160 170 180 QQKGEKIAES YQNILAAIEG SRFYTSDPSQ ACLFVLSLDT LDRDQLSPQY VHNLRSKVQS 190 200 210 220 230 240 LHLWNNGRNH LIFNLYSGTW PDYTEDVGFD IGQAMLAKAS ISTENFRPNF DVSIPLFSKD 250 260 270 280 290 300 HPRTGGERGF LKFNTIPPLR KYMLVFKGKR YLTGIGSDTR NALYHVHNGE DVVLLTTCKH 310 320 330 340 350 360 GKDWQKHKDS RCDRDNTEYE KYDYREMLHN ATFCLVPRGR RLGSFRFLEA LQAACVPVML 370 380 390 400 410 420 SNGWELPFSE VINWNQAAVI GDERLLLQIP STIRSIHQDK ILALRQQTQF LWEAYFSSVE 430 440 450 460 470 480 KIVLTTLEII QDRIFKHISR NSLIWNKHPG GLFVLPQYSS YLGDFPYYYA NLGLKPPSKF 490 500 510 520 530 540 TAVIHAVTPL VSQSQPVLKL LVAAAKSQYC AQIIVLWNCD KPLPAKHRWP ATAVPVVVIE 550 560 570 580 590 600 GESKVMSSRF LPYDNIITDA VLSLDEDTVL STTEVDFAFT VWQSFPERIV GYPARSHFWD 610 620 630 640 650 660 NSKERWGYTS KWTNDYSMVL TGAAIYHKYY HYLYSHYLPA SLKNMVDQLA NCEDILMNFL 670 680 690 700 710 720 VSAVTKLPPI KVTQKKQYKE TMMGQTSRAS RWADPDHFAQ RQSCMNTFAS WFGYMPLIHS 730 740 QMRLDPVLFK DQVSILRKKY RDIERL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1)." Ahn J., Luedecke H.-J., Lindow S., Horton W.A., Lee B., Wagner M.J., Horsthemke B., Wells D.E. Nat. Genet. 11:137-143(1995) [PubMed: 7550340] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Placenta.
[2]	"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: Brain.
[3]	"Genomic organization and promoter structure of the human EXT1 gene." Luedecke H.-J., Ahn J., Lin X., Hill A., Wagner M.J., Schomburg L., Horsthemke B., Wells D.E. Genomics 40:351-354(1997) [PubMed: 9119404] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-320. Tissue: Lung.
[4]	"Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus." Kobayashi S., Morimoto K., Shimizu T., Takahashi M., Kurosawa H., Shirasawa T. Biochem. Biophys. Res. Commun. 268:860-867(2000) [PubMed: 10679296] [Abstract] Cited for: SUBUNIT, SUBCELLULAR LOCATION.
[5]	"The link between heparan sulfate and hereditary bone disease: finding a function for the EXT family of putative tumor suppressor proteins." Duncan G., McCormick C., Tufaro F. J. Clin. Invest. 108:511-516(2001) [PubMed: 11518722] [Abstract] Cited for: FUNCTION.
[6]	"Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes." Wuyts W., Van Hul W. Hum. Mutat. 15:220-227(2000) [PubMed: 10679937] [Abstract] Cited for: REVIEW ON VARIANTS.
[7]	"Spectrum of EXT1 mutations in hereditary multiple exostoses." Raskind W.H., Matsushita M., Conrad E.U. III, Wells D.E., Sandell L.J., Wagner M.J., Houck J. Am. J. Hum. Genet. 59:A280-A280(1996) Cited for: VARIANTS EXT1 GLY-280 AND HIS-340.
[8]	"Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies." Hecht J.T., Hogue D.A., Wang Y., Blanton S.H., Wagner M.J., Strong L.C., Raskind W.H., Hansen M.F., Wells D.E. Am. J. Hum. Genet. 60:80-86(1997) [PubMed: 8981950] [Abstract] Cited for: VARIANT EXT1 LEU-340.
[9]	"Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses." Philippe C., Porter D.E., Emerton M.E., Wells D.E., Simpson A.H.R.W., Monaco A.P. Am. J. Hum. Genet. 61:520-528(1997) [PubMed: 9326317] [Abstract] Cited for: VARIANTS EXT1 ASP-339 AND CYS-340.
[10]	"Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses." Wuyts W., van Hul W., de Boulle K., Hendrickx J., Bakker E., Vanhoenacker F., Mollica F., Luedecke H.-J., Sayli B.S., Pazzaglia U.E., Mortier G., Hamel B.C.J., Conrad E.U. III, Matsushita M., Raskind W.H., Willems P.J. Am. J. Hum. Genet. 62:346-354(1998) [PubMed: 9463333] [Abstract] Cited for: VARIANTS EXT1 GLY-280 AND SER-340.
[11]	"Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses." Raskind W.H., Conrad E.U. III, Matsushita M., Wijsman E.M., Wells D.E., Chapman N., Sandell L.J., Wagner M.J., Houck J. Hum. Mutat. 11:231-239(1998) [PubMed: 9521425] [Abstract] Cited for: VARIANTS EXT1 GLY-280; SER-280; HIS-340 AND HIS-627 DEL.
[12]	"EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas." Bovee J.V.M.G., Cleton-Jansen A.-M., Wuyts W., Caethoven G., Taminiau A.H.M., Bakker E., van Hul W., Cornelisse C.J., Hogendoorn P.C.W. Am. J. Hum. Genet. 65:689-698(1999) [PubMed: 10441575] [Abstract] Cited for: VARIANTS EXT1 HIS-164; 235-PRO--LYS-239 DEL AND SER-316.
[13]	"Mutation analysis of hereditary multiple exostoses in the Chinese." Xu L., Xia J., Jiang H., Zhou J., Li H., Wang D., Pan Q., Long Z., Fan C., Deng H.-X. Hum. Genet. 105:45-50(1999) [PubMed: 10480354] [Abstract] Cited for: VARIANTS EXT1 VAL-486 AND LEU-496.
[14]	"Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes." Bernard M.A., Hall C.E., Hogue D.A., Cole W.G., Scott A., Snuggs M.B., Clines G.A., Luedecke H.-J., Lovett M., Van Winkle W.B., Hecht J.T. Cell Motil. Cytoskeleton 48:149-162(2001) [PubMed: 11169766] [Abstract] Cited for: VARIANT EXT1 215-MET--SER-221 DEL, VARIANT OSTEOCHONDROMA 215-MET--SER-222 DELINS ILE.
[15]	"Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity." Cheung P.K., McCormick C., Crawford B.E., Esko J.D., Tufaro F., Duncan G. Am. J. Hum. Genet. 69:55-66(2001) [PubMed: 11391482] [Abstract] Cited for: CHARACTERIZATION OF VARIANTS, MUTAGENESIS OF GLN-27; ASP-164; ASN-316; ALA-486 AND PRO-496.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

GGDB

GlycoGene database

Cross-references

Sequence databases
EMBLGenBankDDBJ	S79639 mRNA. Translation: AAB62283.1. BC001174 mRNA. Translation: AAH01174.1. U70539 Genomic DNA. Translation: AAC51154.1.
RefSeq	NP_000118.2.
UniGene	Hs.492618
3D structure databases
HSSP	HSSP built from PDB template 1OMX based on UniProtKB Q9ES89.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q16394.
PTM databases
PhosphoSite	Q16394.
Genome annotation databases
Ensembl	ENSG00000182197. Homo sapiens. [Contig view]
GeneID	2131.
KEGG	hsa:2131.
Organism-specific databases
HGNC	HGNC:3512. EXT1.
MIM	133700. phenotype. 150230. phenotype. 215300. phenotype. 608177. gene.
Orphanet	55880. Chondrosarcoma. 321. Exostoses, multiple. 502. Langer-Giedion syndrome.
PharmGKB	PA27924.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOGENOM	Q16394.
HOVERGEN	Q16394.
Gene expression databases
ArrayExpress	Q16394.
CleanEx	HS_EXT1.
GermOnline	ENSG00000182197. Homo sapiens.
Family and domain databases
InterPro	IPR004263. Exostosin. IPR015338. HexNAc_Trfase_a. [Graphical view]
Pfam	PF03016. Exostosin. 1 hit. PF09258. EXTL2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	8611.
SOURCE	Search...

Entry information

Entry name

EXT1_HUMAN

Accession

Primary (citable) accession number: Q16394
Secondary accession number(s): Q9BVI9

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	March 27, 2002
Last modified:	November 25, 2008
This is version 88 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)