Reviewed, UniProtKB/Swiss-Prot P30431 (VMJAR_BOTJA)

Names and origin

Protein names	Recommended name:     Zinc metalloproteinase-disintegrin jararhagin     EC=3.4.24.73 Alternative name(s):     Jararafibrase I       Short name=JF I     JG     HF2-proteinase Cleaved into the following chain:     1- Recommended name:             Disintegrin jararhagin-C         Alternative name(s):             Jaracetin
Organism	Bothrops jararaca (Jararaca)
Taxonomic identifier	8724 [NCBI]
Taxonomic lineage	Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Lepidosauria › Squamata › Scleroglossa › Serpentes › Colubroidea › Viperidae › Crotalinae › Bothrops

Protein attributes

Sequence length	571 AA.
Sequence status	Fragment.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Jararhagin causes hemorrhage. This is the result of the degradation of sub-endothelial matrix proteins leading to the disruption of the blood vessel endothelium, with accompanying disturbances in platelet function. It is able to degrade von Willebrand factor and it hydrolyzes the Aalpha-chain of fibrinogen while leaving the beta and gamma chains unaffected. It inhibits collagen-induced platelet aggregation though the binding of the molecule to the alpha-2 subunit I domain of the platelet surface alpha-2/beta-1 integrin (collagen receptor), and it cleaves the beta-1 subunit of the same integrin, inhibiting platelet interaction and ultimately causing impairment of signal transduction. It has inability to be affected by the plasma inhibitor alpha(2)-macroglobulin. In fibroblasts, it functions as a collagen-mimetic substrate and, in endothelial cells, it causes apoptosis and indirectly inhibits cell proliferation by release of angiostatin-like compounds. It induces a strong pro-inflammatory response characterized by intense leukocyte accumulation and release of cytokines at the site of the injection. Although hemorrhage and edema are a response to the direct effect of this toxin, jararhagin-induced inflammation and necrosis are dependent on macrophages and key pro-inflammatory cytokines or their receptors. It also possesses anti-tumorgenic properties. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 The monomer Jararhagin-C inhibits collagen- and ADP-induced platelet aggregation, but has no effect on glycoprotein Ib-IX-dependent platelet agglutination. Locally activates the early events of an acute inflammatory response as leukocyte rolling and pro-inflammatory cytokine release. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Jaracetin is a dimer representing a differently processed form of jararhagin. It may be a dimeric form of Jararhagin-C. It modulates binding of vWF to the glycoprotein Ib-IX complex on platelets through a specific interaction with the vWF A1 domain. It potently induces platelet aggregation in citrated platelet-rich plasma. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18
Catalytic activity	Cleavage of 10-His-|-Leu-11, 14-Ala-|-Leu-15, 16-Tyr-|-Leu-17 and 24-Phe-|-Phe-25 bonds in insulin B chain. Ref.3
Cofactor	Binds 1 zinc ion per subunit.
Enzyme regulation	Inhibited by EDTA, 1,10 phenanthroline and batimastat (a peptidomimetic MMP inhibitor). Ref.11 Ref.13
Subunit structure	Monomer (Jararhagin and Jararhagin-C) and dimer (Jaracetin). Ref.6
Subcellular location	Secreted.
Tissue specificity	Expressed by the venom gland.
Post-translational modification	The N-terminus of Jararhagin is blocked.
Miscellaneous	The metalloproteinase domain which is released from the cleavage of jararhagin-C is apparently unstable. A third form of jararhagin is obtained when the toxin is submitted to in vitro autolysis. The disintegrin-like/cysteine-rich domains appear to be disulfid-linked to a N-terminal portion of the metalloproteinase domain.
Sequence similarities	Belongs to the venom metalloproteinase family. P-III subfamily. Contains 1 disintegrin domain. Contains 1 peptidase M12B domain.

Ontologies

Keywords
Biological process	Apoptosis Blood coagulation Cell adhesion
Cellular component	Secreted
Ligand	Metal-binding Zinc
Molecular function	Hydrolase Metalloprotease Protease Toxin
PTM	Disulfide bond Glycoprotein Zymogen
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	apoptosis Inferred from electronic annotation. Source: UniProtKB-KW blood coagulation Inferred from electronic annotation. Source: UniProtKB-KW cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW pathogenesis Inferred from electronic annotation. Source: UniProtKB-KW proteolysis Inferred from electronic annotation. Source: InterPro
Cellular component	extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	metalloendopeptidase activity Inferred from electronic annotation. Source: InterPro protein binding Inferred from electronic annotation. Source: UniProtKB-KW zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Propeptide

‹1 – 150

›150

By similarity

PRO_0000029009

Chain

151 – 571

421

Zinc metalloproteinase-disintegrin jararhagin

PRO_0000029010

Chain

360 – 571

212

Disintegrin jararhagin-C

PRO_0000029011

Regions

Domain

159 – 355

197

Peptidase M12B

Domain

363 – 449

87

Disintegrin

Motif

427 – 429

3

D/ECD-tripeptide

Compositional bias

450 – 571

122

Cys-rich

Sites

Active site

296

1

By similarity

Metal binding

295

1

Zinc; catalytic Probable

Metal binding

299

1

Zinc; catalytic Probable

Metal binding

305

1

Zinc; catalytic Probable

Site

339

1

Necessary, but not sufficient, for proteolytic processing

Amino acid modifications

Glycosylation

333

1

N-linked (GlcNAc...) Potential

Disulfide bond

270 ↔ 350

By similarity

Disulfide bond

310 ↔ 334

By similarity

Disulfide bond

312 ↔ 317

By similarity

Disulfide bond

377 ↔ 395

By similarity

Disulfide bond

379 ↔ 390

By similarity

Disulfide bond

389 ↔ 412

By similarity

Disulfide bond

403 ↔ 409

By similarity

Disulfide bond

408 ↔ 434

By similarity

Disulfide bond

421 ↔ 441

By similarity

Experimental info

Non-terminal residue

1

1

Secondary structure

1

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571

Helix Strand Turn

Details...

Beta strand

159 – 167

9

Helix

169 – 174

6

Turn

175 – 177

3

Helix

179 – 197

19

Helix

198 – 200

3

Beta strand

202 – 211

10

Helix

224 – 238

15

Turn

239 – 241

3

Beta strand

246 – 252

7

Beta strand

262 – 264

3

Turn

272 – 274

3

Beta strand

275 – 280

6

Helix

286 – 300

15

Beta strand

311 – 317

7

Helix

333 – 346

14

Helix

350 – 352

3

Sequences

	Sequence		Length	Mass (Da)
	P30431-1 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: F5E549F8BF61177B	FASTA	571	63,983
	10 20 30 40 50 60 ATRPKGAVQP KYEDAMQYEF KVNGEPVVLH LEKNKGLFSK DYSEIHYSPD GREITTYPPV 70 80 90 100 110 120 EDHCYYHGRI ENDADSTASI SACNGLKGYF KLQRETYFIE PLKLPDSEAH AVFKYENVEK 130 140 150 160 170 180 EDEAPKMCGV TQNWKSYEPI KKASQLAFTA EQQRYDPYKY IEFFVVVDQG TVTKNNGDLD 190 200 210 220 230 240 KIKARMYELA NIVNEIFRYL YMHVALVGLE IWSNGDKITV KPDVDYTLNS FAEWRKTDLL 250 260 270 280 290 300 TRKKHDNAQL LTAIDFNGPT IGYAYIGSMC HPKRSVGIVQ DYSPINLVVA VIMAHEMGHN 310 320 330 340 350 360 LGIHHDTGSC SCGDYPCIMG PTISNEPSKF FSNCSYIQCW DFIMNHNPEC IINEPLGTDI 370 380 390 400 410 420 ISPPVCGNEL LEVGEECDCG TPENCQNECC DAATCKLKSG SQCGHGDCCE QCKFSKSGTE 430 440 450 460 470 480 CRASMSECDP AEHCTGQSSE CPADVFHKNG QPCLDNYGYC YNGNCPIMYH QCYALFGADV 490 500 510 520 530 540 YEAEDSCFKD NQKGNYYGYC RKENGKKIPC APEDVKCGRL YCKDNSPGQN NPCKMFYSND 550 560 570 DEHKGMVLPG TKCADGKVCS NGHCVDVATA Y

References

[1]	"Purification, cloning, and molecular characterization of a high molecular weight hemorrhagic metalloprotease, jararhagin, from Bothrops jararaca venom. Insights into the disintegrin gene family." Paine M.J.I., Desmond H.P., Theakston R.D.G., Crampton J.M. J. Biol. Chem. 267:22869-22876(1992) [PubMed: 1385408] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Venom gland.
[2]	"Evidence for heterogeneous forms of the snake venom metalloproteinase jararhagin: a factor contributing to snake venom variability." Moura-da-Silva A.M., Della-Casa M.S., David A.S., Assakura M.T., Butera D., Lebrun I., Shannon J.D., Serrano S.M.T., Fox J.W. Arch. Biochem. Biophys. 409:395-401(2003) [PubMed: 12504907] [Abstract] Cited for: PROTEIN SEQUENCE OF 175-183; 236-242; 361-369; 423-448; 507-516; 520-534 AND 535-552, MISCELLANEOUS.
[3]	"N-terminal amino acid sequences and some characteristics of fibrinolytic/hemorrhagic metalloproteinases purified from Bothrops jararaca venom." Maruyama M., Sugiki M., Anai K., Yoshida E. Toxicon 40:1223-1226(2002) [PubMed: 12165326] [Abstract] Cited for: PROTEIN SEQUENCE OF 213-227; 373-393; 421-439 AND 503-521, CATALYTIC ACTIVITY. Tissue: Venom.
[4]	"A 28 kDa-protein with disintegrin-like structure (jararhagin-C) purified from Bothrops jararaca venom inhibits collagen- and ADP-induced platelet aggregation." Usami Y., Fujimura Y., Miura S., Shima H., Yoshida E., Yoshioka A., Hirano K., Suzuki M., Titani K. Biochem. Biophys. Res. Commun. 201:331-339(1994) [PubMed: 8198592] [Abstract] Cited for: PROTEIN SEQUENCE OF 360-571 (JARARHAGIN-C), FUNCTION OF JARARHAGIN-C. Tissue: Venom.
[5]	"Properties of fibrinogen cleaved by Jararhagin, a metalloproteinase from the venom of Bothrops jararaca." Kamiguti A.S., Slupsky J.R., Zuzel M., Hay C.R.M. Thromb. Haemost. 72:244-249(1994) [PubMed: 7831660] [Abstract] Cited for: FUNCTION.
[6]	"Jararhagin and jaracetin: novel snake venom inhibitors of the integrin collagen receptor, alpha 2 beta 1." De Luca M., Ward C.M., Ohmori K., Andrews R.K., Berndt M.C. Biochem. Biophys. Res. Commun. 206:570-576(1995) [PubMed: 7530003] [Abstract] Cited for: PROTEIN SEQUENCE OF 360-375, FUNCTION, SUBUNIT (JARACETIN). Tissue: Venom.
[7]	"Inhibition of collagen-induced platelet aggregation as the result of cleavage of alpha 2 beta 1-integrin by the snake venom metalloproteinase jararhagin." Kamiguti A.S., Hay C.R.M., Zuzel M. Biochem. J. 320:635-641(1996) [PubMed: 8973578] [Abstract] Cited for: FUNCTION.
[8]	"Collagen-induced secretion-dependent phase of platelet aggregation is inhibited by the snake venom metalloproteinase jararhagin." Kamiguti A.S., Moura-da-Silva A.M., Laing G.D., Knapp T., Zuzel M., Crampton J.M., Theakston R.D.G. Biochim. Biophys. Acta 1335:209-217(1997) [PubMed: 9133658] [Abstract] Cited for: FUNCTION.
[9]	"Selective recognition of alpha2beta1 integrin by jararhagin, a metalloproteinase/disintegrin from Bothrops jararaca venom." Moura-da-Silva A.M., Marcinkiewicz C., Marcinkiewicz M., Niewiarowski S. Thromb. Res. 102:153-159(2001) [PubMed: 11323026] [Abstract] Cited for: FUNCTION.
[10]	"The reprolysin jararhagin, a snake venom metalloproteinase, functions as a fibrillar collagen agonist involved in fibroblast cell adhesion and signaling." Zigrino P., Kamiguti A.S., Eble J., Drescher C., Nischt R., Fox J.W., Mauch C. J. Biol. Chem. 277:40528-40535(2002) [PubMed: 12186858] [Abstract] Cited for: FUNCTION.
[11]	"Pulmonary hemorrhage induced by jararhagin, a metalloproteinase from Bothrops jararaca snake venom." Escalante T., Nunez J., Moura-da-Silva A.M., Rucavado A., Theakston R.D.G., Gutierrez J.M. Toxicol. Appl. Pharmacol. 193:17-28(2003) [PubMed: 14613713] [Abstract] Cited for: FUNCTION, ENZYME REGULATION.
[12]	"Haematopoietic effects induced in mice by the snake venom toxin jararhagin." Maria D.A., Vassao R.C., Ruiz I.R.G. Toxicon 42:579-585(2003) [PubMed: 14602113] [Abstract] Cited for: FUNCTION.
[13]	"Jararhagin, a snake venom metalloproteinase-disintegrin, stimulates epithelial cell migration in an in vitro restitution model." Costa E.P., Santos M.F. Toxicon 44:861-870(2004) [PubMed: 15530968] [Abstract] Cited for: FUNCTION, ENZYME REGULATION.
[14]	"Jararhagin, a snake venom metalloproteinase, induces a specialized form of apoptosis (anoikis) selective to endothelial cells." Tanjoni I., Weinlich R., Della-Casa M.S., Clissa P.B., Saldanha-Gama R.F., de Freitas M.S., Barja-Fidalgo C., Amarante-Mendes G.P., Moura-da-Silva A.M. Apoptosis 10:851-861(2005) [PubMed: 16133875] [Abstract] Cited for: FUNCTION.
[15]	"Role of the snake venom toxin jararhagin in proinflammatory pathogenesis: in vitro and in vivo gene expression analysis of the effects of the toxin." Gallagher P., Bao Y., Serrano S.M.T., Laing G.D., Theakston R.D.G., Gutierrez J.M., Escalante T., Zigrino P., Moura-da-Silva A.M., Nischt R., Mauch C., Moskaluk C., Fox J.W. Arch. Biochem. Biophys. 441:1-15(2005) [PubMed: 16083850] [Abstract] Cited for: FUNCTION.
[16]	"Importance of jararhagin disintegrin-like and cysteine-rich domains in the early events of local inflammatory response." Clissa P.B., Lopes-Ferreira M., Della-Casa M.S., Farsky S.H.P., Moura-da-Silva A.M. Toxicon 47:591-596(2006) [PubMed: 16564063] [Abstract] Cited for: FUNCTION OF JARARHAGIN-C.
[17]	"Toxin jararhagin in low doses induces interstitial edema and increases the metabolic rate and red blood cells in mice." Francisco G., Zara F.J., Maria D.A., Cruz-Neto A.P. Toxicon 48:1060-1067(2006) [PubMed: 17046041] [Abstract] Cited for: FUNCTION.
[18]	"Collagen binding is a key factor for the hemorrhagic activity of snake venom metalloproteinases." Moura-da-Silva A.M., Ramos O.H.P., Baldo C., Niland S., Hansen U., Ventura J.S., Furlan S., Butera D., Della-Casa M.S., Tanjoni I., Clissa P.B., Fernandes I., Chudzinski-Tavassi A.M., Eble J.A. Biochimie 90:484-492(2008) [PubMed: 18096518] [Abstract] Cited for: FUNCTION.
[19]	"Jararhagin and its multiple effects on hemostasis." Laing G.D., Moura-da-Silva A.M. Toxicon 45:987-996(2005) [PubMed: 15922770] [Abstract] Cited for: REVIEW.
[20]	"Crystallization and preliminary X-ray analysis of jararhagin, a metalloproteinase/disintegrin from Bothrops jararaca snake venom." Souza D.H.F., Selistre de Araujo H.S., Moura-da-Silva A.M., Della-Casa M.S., Oliva G., Garratt R.C. Acta Crystallogr. D 57:1135-1137(2001) [PubMed: 11468397] [Abstract] Cited for: CRYSTALLIZATION, 3D-STRUCTURE MODELING.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

X68251 Genomic DNA. Translation: CAA48323.1.

PIR

S24789.

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1C9G	model	-	A	152-355	[»]
3DSL	X-ray	2.70	A/B	153-571	[»]

ModBase

Search...

Protein family/group databases

MEROPS

M12.138.

Phylogenomic databases

HOVERGEN

P30431.

Enzyme and pathway databases

BRENDA

3.4.24.73. 19086.

Family and domain databases

InterPro

IPR006586. ADAM_Cys-rich.
IPR001762. Blood-coag_inhib_Disintegrin.
IPR018358. Disintegrin_CS.
IPR006025. Pept_M_Zn_BS.
IPR001590. Peptidase_M12B.
IPR002870. Peptidase_M12B_N.
[Graphical view]

Gene3D

G3DSA:4.10.70.10. Blood-coag_inhib_Disintegrin. 1 hit.

Pfam

PF08516. ADAM_CR. 1 hit.
PF00200. Disintegrin. 1 hit.
PF01562. Pep_M12B_propep. 1 hit.
PF01421. Reprolysin. 1 hit.
[Graphical view]

PRINTS

PR00289. DISINTEGRIN.

ProDom

PD000664. Disintegrin. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00608. ACR. 1 hit.
SM00050. DISIN. 1 hit.
[Graphical view]

PROSITE

PS50215. ADAM_MEPRO. 1 hit.
PS00427. DISINTEGRIN_1. 1 hit.
PS50214. DISINTEGRIN_2. 1 hit.
PS00142. ZINC_PROTEASE. 1 hit.
[Graphical view]

ProtoNet

Search...

Entry information

Entry name

VMJAR_BOTJA

Accession

Primary (citable) accession number: P30431

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	June 16, 2009
This is version 79 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

Tox-Prot (Toxin Annotation Project)