Reviewed, UniProtKB/Swiss-Prot P00749 (UROK_HUMAN)

Names and origin

Protein names

Urokinase-type plasminogen activator [Precursor]
Also known as:
     EC 3.4.21.73
     U-plasminogen activator
     uPA
Cleaved into:
     Urokinase-type plasminogen activator long chain A
     Urokinase-type plasminogen activator short chain A
     Urokinase-type plasminogen activator chain B

Gene names

Name:

PLAU

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 existence

Evidence at protein level.

General annotation (Comments)

Function	Specifically cleave the zymogen plasminogen to form the active enzyme plasmin.
Catalytic activity	Specific cleavage of Arg-|-Val bond in plasminogen to form plasmin.
Subunit structure	Found in high and low molecular mass forms. Each consists of two chains, A and B. The high molecular mass form contains a long chain A which is cleaved to yield a short chain A. Binds LRP1B; binding is followed by internalization and degradation. Interacts with MRC2. Interacts with PLAUR.
Subcellular location	Secreted.
Tissue specificity	Expressed in the prostate gland and prostate cancers.
Post-translational modification	Phosphorylation of Ser-158 and Ser-323 abolishes proadhesive ability but does not interfere with receptor binding.
Pharmaceutical use	Available under the name Abbokinase (Abbott). Used in Pulmonary Embolism (PE) to initiates fibrinolysis. Clinically used for therapy of thrombolytic disorders.
Sequence similarities	Belongs to the peptidase S1 family. Contains 1 EGF-like domain. Contains 1 kringle domain. Contains 1 peptidase S1 domain.

Ontologies

Keywords
Biological process	Blood coagulation Fibrinolysis Plasminogen activation
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	EGF-like domain Kringle Signal
Molecular function	Hydrolase Protease Serine protease
PTM	Glycoprotein Phosphoprotein Zymogen
Technical term	3D-structure Direct protein sequencing Pharmaceutical
Gene Ontology (GO)
Biological process	chemotaxis Traceable author statement. Source: ProtInc proteolysis Ref.8 Traceable author statement. Source: ProtInc signal transduction Traceable author statement. Source: ProtInc
Cellular component	plasma membrane Inferred from Experiment. Source: Reactome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Signal peptide

1 – 20

20

Chain

21 – 431

411

Urokinase-type plasminogen activator

Chain

21 – 177

157

Urokinase-type plasminogen activator long chain A

Chain

156 – 177

22

Urokinase-type plasminogen activator short chain A

Chain

179 – 431

253

Urokinase-type plasminogen activator chain B

Regions

Domain

27 – 63

37

EGF-like

Domain

70 – 151

82

Kringle

Domain

179 – 424

246

Peptidase S1

Region

34 – 57

24

Binds urokinase plasminogen activator surface receptor By similarity

Region

152 – 177

26

Connecting peptide

Sites

Active site

224

1

Charge relay system

Active site

275

1

Charge relay system

Active site

376

1

Charge relay system

Site

177 – 178

2

Cleavage; during zymogen activation

Amino acid modifications

Modified residue

158

1

Phosphoserine

Modified residue

323

1

Phosphoserine

Glycosylation

38

1

O-linked (Fuc)

Glycosylation

322

1

N-linked (GlcNAc...)

Disulfide bond

31 ↔ 39

Disulfide bond

33 ↔ 51

Disulfide bond

53 ↔ 62

Disulfide bond

70 ↔ 151

Disulfide bond

91 ↔ 133

Disulfide bond

122 ↔ 146

Disulfide bond

168 ↔ 299

Interchain (between A and B chains)

Disulfide bond

209 ↔ 225

Disulfide bond

217 ↔ 288

Disulfide bond

313 ↔ 382

Disulfide bond

345 ↔ 361

Disulfide bond

372 ↔ 400

Natural variations

Natural variant

15

1

V → L

Natural variant

141

1

P → L Rare polymorphism; linked with a decrease in the affinity for fibrin-binding.

Natural variant

214

1

M → I

Natural variant

231

1

K → Q

Experimental info

Mutagenesis

158

1

S → E: Abolishes phosphorylation, proadhesive function and ability to induce chemotactic response; when associated with E-323

Mutagenesis

323

1

S → E: Abolishes phosphorylation, proadhesive function and ability to induce chemotactic response; when associated with E-158

Sequence conflict

151

1

C → W in CAA26535. Ref.4

Sequence conflict

386

1

G → C in CAA26535. Ref.4

Sequence conflict

430

1

A → V in CAA26535. Ref.4

Secondary structure

1

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431

Helix Strand Turn

Details...

Beta strand

71 – 73

3

Beta strand

76 – 78

3

Beta strand

94 – 96

3

Turn

97 – 101

5

Beta strand

102 – 105

4

Helix

109 – 114

6

Beta strand

132 – 139

8

Beta strand

141 – 145

5

Beta strand

147 – 149

3

Beta strand

180 – 184

5

Helix

187 – 189

3

Beta strand

193 – 197

5

Beta strand

207 – 215

9

Beta strand

218 – 221

4

Helix

223 – 225

3

Turn

226 – 228

3

Helix

232 – 234

3

Beta strand

236 – 240

5

Beta strand

243 – 246

4

Beta strand

252 – 261

10

Beta strand

277 – 282

6

Beta strand

312 – 318

7

Beta strand

333 – 340

8

Helix

342 – 345

4

Turn

348 – 351

4

Helix

352 – 354

3

Beta strand

359 – 363

5

Beta strand

379 – 383

5

Beta strand

385 – 396

12

Beta strand

398 – 402

5

Beta strand

407 – 411

5

Helix

412 – 414

3

Helix

416 – 422

7

Sequences

	Sequence		Length	Mass (Da)
	P00749-1 [UniParc]. Last modified March 20, 1987. Version 1. Checksum: BAA9A6ACD2A353F1	FASTA	431	48,525
	10 20 30 40 50 60 MRALLARLLL CVLVVSDSKG SNELHQVPSN CDCLNGGTCV SNKYFSNIHW CNCPKKFGGQ 70 80 90 100 110 120 HCEIDKSKTC YEGNGHFYRG KASTDTMGRP CLPWNSATVL QQTYHAHRSD ALQLGLGKHN 130 140 150 160 170 180 YCRNPDNRRR PWCYVQVGLK PLVQECMVHD CADGKKPSSP PEELKFQCGQ KTLRPRFKII 190 200 210 220 230 240 GGEFTTIENQ PWFAAIYRRH RGGSVTYVCG GSLMSPCWVI SATHCFIDYP KKEDYIVYLG 250 260 270 280 290 300 RSRLNSNTQG EMKFEVENLI LHKDYSADTL AHHNDIALLK IRSKEGRCAQ PSRTIQTICL 310 320 330 340 350 360 PSMYNDPQFG TSCEITGFGK ENSTDYLYPE QLKMTVVKLI SHRECQQPHY YGSEVTTKML 370 380 390 400 410 420 CAADPQWKTD SCQGDSGGPL VCSLQGRMTL TGIVSWGRGC ALKDKPGVYT RVSHFLPWIR 430 SHTKEENGLA L

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The human urokinase-plasminogen activator gene and its promoter." Riccio A., Grimaldi G., Verde P., Sebastio G., Boast S., Blasi F. Nucleic Acids Res. 13:2759-2771(1985) [PubMed: 2987867] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[2]	"Cloning and expression of the gene for pro-urokinase in Escherichia coli." Holmes W.E., Pennica D., Blaber M., Rey M.W., Guenzler W.A., Steffens G.J., Heyneker H.L. Biotechnology (N.Y.) 3:923-929(1985) Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Molecular cloning of cDNA coding for human preprourokinase." Nagai M., Hiramatsu R., Kaneda T., Hayasuke N., Arimura H., Nishida M., Suyama T. Gene 36:183-188(1985) [PubMed: 2415429] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Molecular cloning, sequencing, and expression in Escherichia coli of human preprourokinase cDNA." Jacobs P., Cravador A., Loriau R., Brockly F., Colau B., Chuchana P., van Elsen A., Herzog A., Bollen A. DNA 4:139-146(1985) [PubMed: 3888571] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	SeattleSNPs program for genomic applications Submitted (JUN-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS LEU-15; LEU-141 AND GLN-231.
[6]	"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: Lung.
[7]	"Characterization of a posttranslational fucosylation in the growth factor domain of urinary plasminogen activator." Buko A.M., Kentzer E.J., Petros A., Menon G., Zuiderweg E.R., Sarin V.K. Proc. Natl. Acad. Sci. U.S.A. 88:3992-3996(1991) [PubMed: 2023947] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-43, GLYCOSYLATION AT THR-38, MASS SPECTROMETRY.
[8]	"Identification and primary sequence of an unspliced human urokinase poly(A)+ RNA." Verde P., Stoppelli M.P., Galeffi P., di Nocera P., Blasi F. Proc. Natl. Acad. Sci. U.S.A. 81:4727-4731(1984) [PubMed: 6589620] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] OF 66-431.
[9]	"The primary structure of high molecular mass urokinase from human urine. The complete amino acid sequence of the A chain." Gunzler W.A., Steffens G.J., Otting F., Kim S.-M.A., Frankus E., Flohe L. Hoppe-Seyler's Z. Physiol. Chem. 363:1155-1165(1982) [PubMed: 6754569] [Abstract] Cited for: PROTEIN SEQUENCE OF 21-177.
[10]	"Human low-molecular-weight urinary urokinase. Partial characterization and preliminary sequence data of the two polypeptide chains." Schaller J., Nick H., Rickli E.E., Gillessen D., Lergier W., Studer R.O. Eur. J. Biochem. 125:251-257(1982) [PubMed: 6749491] [Abstract] Cited for: PROTEIN SEQUENCE OF 156-176 AND 179-224.
[11]	"The complete amino acid sequence of low molecular mass urokinase from human urine." Steffens G.J., Gunzler W.A., Otting F., Frankus E., Flohe L. Hoppe-Seyler's Z. Physiol. Chem. 363:1043-1058(1982) [PubMed: 6754572] [Abstract] Cited for: PROTEIN SEQUENCE OF 158-410.
[12]	"Phosphorylation of human pro-urokinase on Ser138/303 impairs its receptor-dependent ability to promote myelomonocytic adherence and motility." Franco P., Iaccarino C., Chiaradonna F., Brandazza A., Iavarone C., Mastronicola M.R., Nolli M.L., Stoppelli M.P. J. Cell Biol. 137:779-791(1997) [PubMed: 9151681] [Abstract] Cited for: PHOSPHORYLATION AT SER-158 AND SER-323, MUTAGENESIS OF SER-158 AND SER-323.
[13]	"A urokinase receptor-associated protein with specific collagen binding properties." Behrendt N., Jensen O.N., Engelholm L.H., Moertz E., Mann M., Danoe K. J. Biol. Chem. 275:1993-2002(2000) [PubMed: 10636902] [Abstract] Cited for: INTERACTION WITH MRC2.
[14]	"The putative tumor suppressor LRP1B, a novel member of the low density lipoprotein (LDL) receptor family, exhibits both overlapping and distinct properties with the LDL receptor-related protein." Liu C.-X., Li Y., Obermoeller-McCormick L.M., Schwartz A.L., Bu G. J. Biol. Chem. 276:28889-28896(2001) [PubMed: 11384978] [Abstract] Cited for: INTERACTION WITH LRP1B.
[15]	"Platelet-derived growth factor D is activated by urokinase plasminogen activator in prostate carcinoma cells." Ustach C.V., Kim H.-R.C. Mol. Cell. Biol. 25:6279-6288(2005) [PubMed: 15988036] [Abstract] Cited for: TISSUE SPECIFICITY.
[16]	"Dynamics of the multidomain fibrinolytic protein urokinase from two-dimensional NMR." Oswald R.E., Bogusky M.J., Bamberger M., Smith R.A.G., Dobson C.M. Nature 337:579-582(1989) [PubMed: 2536903] [Abstract] Cited for: STRUCTURE BY NMR.
[17]	"Sequential 1H NMR assignments and secondary structure of the kringle domain from urokinase." Li X., Smith R.A.G., Dobson C.M. Biochemistry 31:9562-9571(1992) [PubMed: 1327118] [Abstract] Cited for: STRUCTURE BY NMR OF 67-155.
[18]	"Solution structure of the kringle domain from urokinase-type plasminogen activator." Li X., Bokman A.M., Llinas M., Smith R.A.G., Dobson C.M. J. Mol. Biol. 235:1548-1559(1994) [PubMed: 8107091] [Abstract] Cited for: STRUCTURE BY NMR OF 67-155.
[19]	"The crystal structure of the catalytic domain of human urokinase-type plasminogen activator." Spraggon G.,