Roles of lysine residues and N-terminal α-amino group in membrane-damaging activity of Taiwan cobra cardiotoxin 3 toward anionic and zwitterionic phospholipid vesicles

In contrast to a slight increase in activity toward phosphatidylcholine (EYPC)/dimyristoyl phosphatidic acid (DMPA) vesicles, guanidination of Naja naja atra cardiotoxin 3 (CTX3) and selective trinitrophenylation of N-terminal α-amino group enhanced notably membrane-damaging activity on EYPC/egg yol...

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Bibliographic Details
Published in:Toxicon (Oxford) 2010-02, Vol.55 (2), p.256-264
Main Authors: Chiou, Yi-Ling, Kao, Pei-Hsiu, Liu, Wen-Hsin, Lin, Shinne-Ren, Chang, Long-Sen
Format: Article
Language:English
Subjects:
Animal poisons toxicology. Antivenoms
Biological and medical sciences
Cardiotoxin
Circular Dichroism
Cobra Cardiotoxin Proteins - chemistry
Cobra Cardiotoxin Proteins - toxicity
Colorimetry
Drug Screening Assays, Antitumor
Elapid Venoms - chemistry
Elapid Venoms - toxicity
Erythrocytes - drug effects
Fluorescent Dyes
Guanidines - chemistry
Hemolysis - drug effects
Humans
In Vitro Techniques
Lipids - chemistry
Liposomes - chemistry
Lysine - chemistry
Medical sciences
Membrane-bound mode
Membrane-damaging activity
Membranes - chemistry
Membranes - drug effects
Phosphatidylcholines - chemistry
Phospholipid component
Phospholipids - chemistry
Rhodamines
Sphingomyelins - chemistry
Structure-Activity Relationship
Toxicology
U937 Cells
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Summary:In contrast to a slight increase in activity toward phosphatidylcholine (EYPC)/dimyristoyl phosphatidic acid (DMPA) vesicles, guanidination of Naja naja atra cardiotoxin 3 (CTX3) and selective trinitrophenylation of N-terminal α-amino group enhanced notably membrane-damaging activity on EYPC/egg yolk sphingomyelin (EYSM) vesicles. Chemically modified CTX3 showed a reduction in its hemolytic activity and cytotoxicity. These reflected that membrane-damaging activity of CTX3 was affected by phospholipid compositions. Phospholipid-binding capability and oligomeric assembly upon binding with lipid vesicles did not closely correlate with membrane-damaging potency of native and modified CTX3. Moreover, different topographical contacts and distinctive modes for the binding of CTX3 and its modified derivatives with anionic phospholipid vesicles (EYPC/DMPA) and zwitterionic phospholipid vesicles (EYPC/EYSM) were observed. Compared with in the case of EYPC/DMPA, the interaction between CTX molecules and EYPC/EYSM was drastically reduced by increasing salt concentration and heparin. Taken together, our data indicate that guanidination of Lys residues and trinitrophenylation of α-amino group alter differently the interacted modes upon absorption on anionic phospholipid vesicles and zwitterionic phospholipid vesicles. The findings also suggest that positively charged residues of CTX3 play a distinctive role in damaging anionic and zwitterionic phospholipid vesicles.
ISSN:0041-0101
1879-3150
DOI:10.1016/j.toxicon.2009.07.032