Cytotoxin 3
Identifiers
OrganismNaja atra
Symbol?
PDB1H0J
UniProtP60301
Search for
StructuresSwiss-model
DomainsInterPro

Cardiotoxin III (CTX III, also known as cytotoxin 3) is a sixty amino-acid polypeptide toxin from the Taiwan Cobra Naja atra. CTX III is highly basic and hydrophobic protein.[1] It is an example of a group of snake cardio/cytotoxins (InterPro: IPR003572), which are made up of shorter snake venom three-finger toxins. Over 50 different cytotoxin polypeptides have been isolated and sequenced from venom samples. The difference in the CTX functionality may be due to the relatively small difference in the polypeptide's structure, allowing different CTXs to induce lysis in different cell types.[2] The CTX III molecule contains multiple binding sites and is cytolytic for myocardial cells and human leukemic T cells.[3]

CTX III's molecular structure displays a folding of the polypeptide backbone that creates five stands from a globular structure. These strands form a double and a triple antiparallel β-sheet.[4] Studies performed with an antibody complementary of CTX III seemed to conclude that the active site for the molecule's hemolytic and cytotoxic functions and characteristics result from two separate sites.

Biological research

Cardiotoxin III pathway to induce apoptosis in U937, human leukemia cells.

Recent evidence has shown that CTX III may induce apoptosis in K562 cells via the release of cytochrome c. Results indicate that the mechanism utilized by CTX III was a ROS-independent mitochondrial dysfunction pathway. Evidence from a Taiwanese study of CTX III suggest that the polypeptide selectively enhances apoptosis induction in CD8+ T cells.[5] Another study performed using MDA-MB-231 breast cancer cells concluded that CTX III could induce apoptosis via concomitant inactivation of the JAK2, STAT3, PI3K, and Akt signaling pathways.[6] In Colo205, human colorectal cancer cells, CTX III was found to induce apoptosis. HepG2, a type of carcinoma cell found in humans, was found to undergo apoptosis through S phase arrest when exposed to isolated toxin samples.[7] The toxin's membrane disturbing activity was found not necessary in inducing cell death in a study using U937 cells via the Ca2+/PP2A/AMPK axis.[8]

References

  1. ↑ Su, Shu-Hui; Su, Shu-Jem; Lin, Shinne-Ren; Chang, Kee-Lung (November 2003). "Cardiotoxin-III selectively enhances activation-induced apoptosis of human CD8+ T lymphocytes". Toxicology and Applied Pharmacology. 193 (1): 97–105. doi:10.1016/S0041-008X(03)00327-2. PMID 14613720.
  2. ↑ Ménez, A.; Gatineau, E.; Roumestand, C.; Harvey, A.L.; Mouawad, L.; Gilquin, B.; Toma, F. (August 1990). "Do cardiotoxins possess a functional site? Structural and chemical modification studies reveal the functional site of the cardiotoxin from Naja nigricollis". Biochimie. 72 (8): 575–588. doi:10.1016/0300-9084(90)90121-v. ISSN 0300-9084. PMID 2126462.
  3. ↑ Sivaraman, T.; Kumar, T. K. S.; Huang, C. C.; Yu, C. (January 1998). "The role of acetic acid in the prevention of salt-induced aggregation of snake venom cardiotoxins". IUBMB Life. 44 (1): 29–39. doi:10.1080/15216549800201032. ISSN 1521-6543. PMID 9503145. S2CID 28326180.
  4. ↑ Bhaskaran, Rajagopalan; Huang, Chung Chih; Chang, Ding Kwo; Yu, Chin (1994-01-27). "Cardiotoxin III from the Taiwan Cobra (Naja naja atra): Determination of Structure in Solution and Comparison with Short Neurotoxins". Journal of Molecular Biology. 235 (4): 1291–1301. doi:10.1006/jmbi.1994.1082. ISSN 0022-2836. PMID 8308891.
  5. ↑ Su, Shu-Hui; Su, Shu-Jem; Lin, Shinne-Ren; Chang, Kee-Lung (2003-11-15). "Cardiotoxin-III selectively enhances activation-induced apoptosis of human CD8+ T lymphocytes". Toxicology and Applied Pharmacology. 193 (1): 97–105. doi:10.1016/S0041-008X(03)00327-2. ISSN 0041-008X. PMID 14613720.
  6. ↑ Lin, Kuei-Li; Su, Jung-Chen; Chien, Ching-Ming; Chuang, Pei-Wen; Chang, Long-Sen; Lin, Shinne-Ren (2010-06-15). "Down-regulation of the JAK2/PI3K-mediated signaling activation is involved in Taiwan cobra cardiotoxin III-induced apoptosis of human breast MDA-MB-231 cancer cells". Toxicon. 55 (7): 1263–1273. doi:10.1016/j.toxicon.2010.01.017. ISSN 0041-0101. PMID 20144642.
  7. ↑ Chen, Xingyong; Lv, Ping; Liu, Jing; Xu, Kangsen (2009-07-01). "Apoptosis of human hepatocellular carcinoma cell (HepG2) induced by cardiotoxin III through S-phase arrest". Experimental and Toxicologic Pathology. 61 (4): 307–315. doi:10.1016/j.etp.2008.09.006. ISSN 0940-2993. PMID 18986802.
  8. ↑ Chiou, Jing-Ting; Shi, Yi-Jun; Wang, Liang-Jun; Huang, Chia-Hui; Lee, Yuan-Chin; Chang, Long-Sen (September 2019). "Naja atra Cardiotoxin 3 Elicits Autophagy and Apoptosis in U937 Human Leukemia Cells through the Ca2+/PP2A/AMPK Axis". Toxins. 11 (9): 527. doi:10.3390/toxins11090527. ISSN 2072-6651. PMC 6784133. PMID 31547294.


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