Basic amino acid residues in the β-structure region contribute, but not critically, to presynaptic neurotoxicity of ammodytoxin A

Ivanovski, Gabriela; Petan, Toni; Križaj, Igor; Gelb, Michael H.; Gubenšek, Franc; Pungerčar, Jože

doi:10.1016/j.bbapap.2004.09.002

Cited by 10 publications

(9 citation statements)

References 46 publications

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“…Similarly, two basic residues at nearly equivalent positions in the hGIIA enzyme, Arg7 and Lys10, were shown to have a negative influence on interfacial binding Snitko et al, 1997). In agreement with this, we have shown that the substitution of Arg at position 72 of the IBS of Atxs and DPLA 2 has a positive impact on interfacial binding and activity only upon introduction of a hydrophobic (Ile), but not a polar (Ser), acidic (Glu) or other basic (Lys) residue (Ivanovski et al, 2004). An additional, albeit smaller, negative effect on interfacial binding and enzymatic activity of DPLA 2 is provided by the presence of the polar residue Ser24 instead of the aromatic and hydrophobic Phe in AtxA (Petan et al, 2002(Petan et al, , 2005.…”

Section: Role Of Different Ibs Residues In Supporting Interfacial Binsupporting

confidence: 73%

“…By substituting several basic residues in the C-terminal region (AtxA NNTETE mutant: AtxA-K108N/K111N/K127T/K128E/E129T/K132E) and in the ß-structure region (AtxA SSL mutant: AtxA-K74S/H76S/R77L) with acidic and non-ionic residues, we have shown, contrary to previous beliefs, that the basic character of Atxs, and probably of other ß-neurotoxic sPLA 2 s, is not obligatory for presynaptic toxicity (Ivanovski et al, 2004;Prijatelj et al, 2000; Table 1). According to our earlier structure-function analyses, the more than one order of magnitude lower toxicity of AtxC than that of AtxA is a consequence of the substitution of the aromatic Phe124 by Ile (Pungerčar et al, 1999).…”

Section: Structural Determinants Of Presynaptic Neurotoxicity Of Splacontrasting

confidence: 50%

“…Our structure-function studies of ß-neurotoxic sPLA 2 s (Ivanovski et al, 2000(Ivanovski et al, , 2004Petan et al, 2002Petan et al, , 2005Prijatelj et al, 2000Prijatelj et al, , 2002Prijatelj et al, , 2003Prijatelj et al, , 2006bPrijatelj et al, , 2008Pungerčar et al, 1999) clearly show that different parts of the toxin molecule have separate roles in the distinct steps of the complex mechanism of presynaptic neurotoxicity . Most significantly, by selectively mutating parts of the DPLA 2 molecule, we were able to map the residues that separate the weakly ß-neurotoxic sPLA 2 from the 150-fold more potent AtxA (Prijatelj et al, 2008).…”

Section: Structural Determinants Of Presynaptic Neurotoxicity Of Splamentioning

confidence: 99%

“…of at least five independent measurements. Data taken from Ivanovski et al (2004), Petan et al (2005Petan et al ( , 2007, Prijatelj et al (2006b.…”

Section: Interaction Of Atxs With High-affinity Binding Proteinsmentioning

confidence: 99%

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Protein Engineering in Structure-Function Studies of Viper's Venom Secreted Phospholipases A2

Petan¹,

Žnidaršič²,

Pungerčar³

2013

Genetic Manipulation of DNA and Protein - Examples From Current Research

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Section: Role Of Different Ibs Residues In Supporting Interfacial Binsupporting

confidence: 73%

Section: Structural Determinants Of Presynaptic Neurotoxicity Of Splacontrasting

confidence: 50%

Section: Structural Determinants Of Presynaptic Neurotoxicity Of Splamentioning

confidence: 99%

“…of at least five independent measurements. Data taken from Ivanovski et al (2004), Petan et al (2005Petan et al ( , 2007, Prijatelj et al (2006b.…”

Section: Interaction Of Atxs With High-affinity Binding Proteinsmentioning

confidence: 99%

See 2 more Smart Citations

Protein Engineering in Structure-Function Studies of Viper's Venom Secreted Phospholipases A2

Petan¹,

Žnidaršič²,

Pungerčar³

2013

Genetic Manipulation of DNA and Protein - Examples From Current Research

Self Cite

View full text Add to dashboard Cite

“…Additional relevant material can be cited (Qin and Kostic, 1992; Gomez‐Moreno et al, 1998; Cunha et al, 1999; Ivanoversuski et al, 2004).…”

Section: Mechanismmentioning

confidence: 99%

Protein electron transfer (mechanism and reproductive toxicity): Iminium, hydrogen bonding, homoconjugation, amino acid side chains (redox and charged), and cell signaling

Kovacic

2007

Birth Defects Research Pt C

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This contribution presents novel biochemical perspectives of protein electron transfer (ET) with focus on the iminium nature of the peptide link, along with relationships to reproductive toxicity. The favorable influence of hydrogen bonding on protein ET has been widely documented. Hydrogen bonding of the zwitterionic peptide enhances iminium character. A wide array of such bonding agents is available in vivo, with many reports on the peptide link itself. ET proceeds along the backbone, due in part, to homoconjugation. Redox amino acids (AAs), mainly tyrosine (Tyr), tryptophan (Typ), histidine (His), cysteine (Cys), disulfide, and methionine (Met), are involved in the competing processes for radical formation: direct hydrogen atom abstraction versus electron and proton loss. It appears that the radical or radical cation generated during the redox process is capable of interacting with n-electrons of the backbone. Beneficial effects of cationic AAs impact the conduction process. A relationship apparently exists involving cell signaling, protein conduction, and radicals or electrons. In addition, the link between protein ET and reproductive toxicity is examined. A key element is the role of reactive oxygen species (ROS) generated by protein ET. There is extensive evidence for involvement of ROS in generation of birth defects. The radical species arise in protein mainly by ET transformations by enzymes, as illustrated in the case of alcoholism.

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Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

Montecucco

Gutiérrez

Lomonte

2008

Cell. Mol. Life Sci.

258

163

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A large variety of snake toxins evolved from PLA(2) digestive enzymes through a process of 'accelerated evolution'. These toxins have different tissue targets, membrane receptors and mechanisms of alteration of the cell plasma membrane. Two of the most commonly induced effects by venom PLA(2)s are neurotoxicity and myotoxicity. Here, we will discuss how these snake toxins achieve a similar cellular lesion, which is evolutionarily highly conserved, despite the differences listed above. They cause an initial plasma membrane perturbation which promotes a large increase of the cytosolic Ca(2+) concentration leading to cell degeneration, following modes that we discuss in detail for muscle cells and for the neuromuscular junction. The different systemic pathophysiological consequences caused by these toxins are not due to different mechanisms of cell toxicity, but to the intrinsic anatomical and physiological properties of the targeted tissues and cells.

show abstract

Basic amino acid residues in the β-structure region contribute, but not critically, to presynaptic neurotoxicity of ammodytoxin A

Cited by 10 publications

References 46 publications

Protein Engineering in Structure-Function Studies of Viper's Venom Secreted Phospholipases A2

Protein Engineering in Structure-Function Studies of Viper's Venom Secreted Phospholipases A2

Protein electron transfer (mechanism and reproductive toxicity): Iminium, hydrogen bonding, homoconjugation, amino acid side chains (redox and charged), and cell signaling

Cellular pathology induced by snake venom phospholipase A2 myotoxins and neurotoxins: common aspects of their mechanisms of action

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