Atrolysin A

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Atrolysin A
Identifiers
EC no. 3.4.24.1
CAS no. 37288-82-7
Databases
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BRENDA BRENDA entry
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KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
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NCBI proteins
Zinc metalloproteinase-disintegrin-like atrolysin-A
Identifiers
Organism Crotalus atrox
SymbolN/A
CAS number 37288-82-7
UniProt Q92043
Other data
EC number 3.4.24.1
Search for
Structures Swiss-model
Domains InterPro

Atrolysin A (EC 3.4.24.1) is an enzyme that is one of six hemorrhagic toxins found in the venom of western diamondback rattlesnake. This endopeptidase has a length of 419 amino acid residues. [1] [2] [3] [4] The metalloproteinase disintegrin-like domain and the cysteine-rich domain of the enzyme are responsible for the enzyme's hemorrhagic effects on organisms via inhibition of platelet aggregation. [5] [6] [7]

Contents

This enzyme catalyzes the following chemical reactions:

Nomenclature

The accepted name for this enzyme is Atrolysin A. The enzyme is also known by:

Structure

The amino acid sequence of atrolysin A is 419 sequences long, and contains ten calcium binding sites between positions 9 and 225, three of which are catalytic histidine residues at positions 142, 146, and 152. [6] There are also three positions (142, 146, 152) that are used for binding with the enzyme's cofactor, zinc. The active site lies at position 143. [6]

3D rendering of the atrolysin A protein from SWISS-MODEL. The gold bands represent cysteine. The green spheres represent calcium ions at their binding sites, while the purple sphere represents the enzyme's cofactor, zinc, at its binding site. Atrolysin A structure.png
3D rendering of the atrolysin A protein from SWISS-MODEL. The gold bands represent cysteine. The green spheres represent calcium ions at their binding sites, while the purple sphere represents the enzyme's cofactor, zinc, at its binding site.

A significant portion of the protein from position 1-190 consists of alpha-helical structures with two shorted helixes between positions 315-340. [6] There are 39 observed disulfide bonds in the protein, all but one of these disulfide bonds occur between positions 157-409. Research suggests that the RSECD cysteine residue at positions 272-276 must be involved in a disulfide bond for the enzyme to have an inhibitory effect on platelet aggregation. [6]

The protein contains the following three domains:

Mechanisms of action

The metalloproteinase disintegrin-like domain has shown an ability to degrade sub-endothelial matrix proteins such as type IV collagen, and fibronectin [6] which is partially responsible for the hemorrhage caused by the toxin

The cysteine-rich domain binds to the alpha-2/beta-1 integrin and causes inhibition of the platelet aggregation pathways that collagen is responsible for. [7] [6] The glycoprotein VI (GPVI) collagen receptor however, does not seem affected by atrolysin A or other snake venom metalloproteinases (SVMP ). [9] Other agonists for platelet formation and aggregation such as adenosine diphosphate (ADP) or pathways mediated by convulxin also do not seem inhibited by the toxin in most organisms. [6] [10] [11] The cysteine-rich domain was shown to have two sequences that cause an interaction which prevents alpha-2/beta-1 integrin expressing K562 cells and platelets from binding to collagen. [9]

This enzyme may have the potential to inhibit platelet formation with certain pathways that were previously determined that the toxin had no effect on. For example, ADP stimulated aggregation appears to be inhibited by atrolysin A in a study where insect cells were used to express the protein, and the protein was inserted into human blood. When this variant of the protein was inserted into human blood, ADP stimulated platelet aggregation was inhibited. [5] This form of platelet aggregation does not appear inhibited by atrolysin A in other studies. This suggests that there may be an interaction between the disintegrin-like domain, and cysteine-rich domain of atrolysin A and fibrinogen receptor alpha-2b/beta-3 as well as the collagen receptor. [5]

Isozymes

Other atrolysin isozymes (A-F) have been further studied to understand potential methods of treatment against SVMPs. Research has been conducted on the use of medications to treat other diseases such as arthritis, and tumor metastasis as well. [12]

Related Research Articles

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<span class="mw-page-title-main">Disintegrin</span> Proteins from viper venom inhibiting platelets aggregation

Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion.

<span class="mw-page-title-main">Convulxin</span> Snake venom toxin

Convulxin is a snake venom toxin found in a tropical rattlesnake known as Crotalus durissus terrificus. It belongs to the family of hemotoxins, which destroy red blood cells or, as is the case with convulxin, induce blood coagulation.

<span class="mw-page-title-main">Western diamondback rattlesnake</span> Species of snake

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<span class="mw-page-title-main">ADAM (protein)</span>

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<span class="mw-page-title-main">Platelet glycoprotein VI</span> Protein-coding gene in the species Homo sapiens

Platelet glycoprotein VI (GPVI) is a glycoprotein receptor for collagen which is expressed in platelets. In humans, glycoprotein VI is encoded by the GP6 gene. It was first cloned in 2000 by several groups including that of Martine Jandrot-Perrus from INSERM.

<span class="mw-page-title-main">MMP7</span> Protein-coding gene in humans

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

<span class="mw-page-title-main">ADAMTS4</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ADAM12</span> Human protein-coding gene

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<span class="mw-page-title-main">ADAM10</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">ADAM22</span> Enzyme found in humans

Disintegrin and metalloproteinase domain-containing protein 22, also known as ADAM22, is an enzyme that in humans is encoded by the ADAM22 gene.

<span class="mw-page-title-main">ADAM23</span> Protein-coding gene in the species Homo sapiens

Disintegrin and metalloproteinase domain-containing protein 23 is a non-catalytic protein that in humans is encoded by the ADAM23 gene. It is a member of the ADAM family of extracellular matrix metalloproteinases.

<span class="mw-page-title-main">ADAM28</span> Protein-coding gene in the species Homo sapiens

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Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

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Atrolysin B is an enzyme. This enzyme catalyses the following chemical reaction

Atrolysin C is an enzyme. This enzyme catalyses the following chemical reaction

Atrolysin E is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">ADAM20</span> Protein-coding gene in the species Homo sapiens

Disintegrin and metalloproteinase domain-containing protein 20 is an enzyme that in humans is encoded by the ADAM20 gene. It is a membrane disintegrin-metalloprotease that belongs to the ADAM family. It is exclusively expressed in Testes and is similar to sperm cell-specific fertilins -alpha and -beta.

References

  1. ↑ Bjarnason JB, Tu AT (August 1978). "Hemorrhagic toxins from Western diamondback rattlesnake (Crotalus atrox) venom: isolation and characterization of five toxins and the role of zinc in hemorrhagic toxin e". Biochemistry. 17 (16): 3395–3404. doi:10.1021/bi00609a033. PMID   210790.
  2. ↑ Mori N, Nikai T, Sugihara H, Tu AT (February 1987). "Biochemical characterization of hemorrhagic toxins with fibrinogenase activity isolated from Crotalus ruber ruber venom". Archives of Biochemistry and Biophysics. 253 (1): 108–121. doi:10.1016/0003-9861(87)90643-6. PMID   2949699.
  3. ↑ Bjarnason JB, Hamilton D, Fox JW (May 1988). "Studies on the mechanism of hemorrhage production by five proteolytic hemorrhagic toxins from Crotalus atrox venom". Biological Chemistry Hoppe-Seyler. 369 (Suppl): 121–129. PMID   3060135.
  4. ↑ Bjarnason JB, Fox JW (1989). "Hemorrhagic toxins from snake venoms". Journal of Toxicology: Toxin Reviews. 7 (2): 121–209. doi:10.3109/15569548809059729.
  5. 1 2 3 4 Jia LG, Wang XM, Shannon JD, Bjarnason JB, Fox JW (May 1997). "Function of disintegrin-like/cysteine-rich domains of atrolysin A. Inhibition of platelet aggregation by recombinant protein and peptide antagonists". The Journal of Biological Chemistry. 272 (20): 13094–13102. doi: 10.1074/jbc.272.20.13094 . PMID   9148922.
  6. 1 2 3 4 5 6 7 8 "Zinc metalloproteinase-disintegrin-like atrolysin-A - Crotalus atrox (Western diamondback rattlesnake)". www.uniprot.org. Retrieved 2021-10-29.
  7. 1 2 Serrano SM, Jia LG, Wang D, Shannon JD, Fox JW (October 2005). "Function of the cysteine-rich domain of the haemorrhagic metalloproteinase atrolysin A: targeting adhesion proteins collagen I and von Willebrand factor". The Biochemical Journal. 391 (Pt 1): 69–76. doi:10.1042/BJ20050483. PMC   1237140 . PMID   15929722.
  8. ↑ "Protein: VM3AA_CROAT (Q92043)". InterPro. European Molecular Biology Laboratory.
  9. 1 2 Kamiguti AS, Gallagher P, Marcinkiewicz C, Theakston RD, Zuzel M, Fox JW (August 2003). "Identification of sites in the cysteine-rich domain of the class P-III snake venom metalloproteinases responsible for inhibition of platelet function". FEBS Letters. 549 (1–3): 129–134. doi: 10.1016/S0014-5793(03)00799-3 . PMID   12914938.
  10. ↑ Puri RN, Colman RW (1997). "ADP-induced platelet activation". Critical Reviews in Biochemistry and Molecular Biology. 32 (6): 437–502. doi:10.3109/10409239709082000. PMID   9444477.
  11. ↑ Francischetti IM, Ghazaleh FA, Reis RA, Carlini CR, Guimarães JA (May 1998). "Convulxin induces platelet activation by a tyrosine-kinase-dependent pathway and stimulates tyrosine phosphorylation of platelet proteins, including PLC gamma 2, independently of integrin alpha IIb beta 3". Archives of Biochemistry and Biophysics. 353 (2): 239–250. doi:10.1006/abbi.1998.0598. PMID   9606958.
  12. ↑ Zhang D, Botos I, Gomis-Rüth FX, Doll R, Blood C, Njoroge FG, et al. (August 1994). "Structural interaction of natural and synthetic inhibitors with the venom metalloproteinase, atrolysin C (form d)". Proceedings of the National Academy of Sciences of the United States of America. 91 (18): 8447–8451. doi:10.1073/pnas.91.18.8447. PMC   44623 . PMID   8078901.
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