Identification of continuous interaction sites in PLA2-based protein complexes by peptide arrays

Fortes-Dias, Consuelo Latorre; Santos, Roberta Márcia Marques dos; Magro, Ângelo J.; Fontes, Marcos R.M.; Chávez-Olórtegui, Carlos; Granier, Claude

doi:10.1016/j.biochi.2009.08.006

Cited by 18 publications

(8 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, it was indicated that chemical modification of Tyr22 from CB reduced its neurotoxicity and binding affinity for presynaptic membranes27. Finally, peptide-array analysis showed that the N-terminal region of CB (Phe11-Ala18) could constitute a pharmacological site of this protein71. Thus, as CA enhances the toxicity of CB at the neuromuscular junction, targeting CB to the target sites, it is possible to suggest that in the CTX heterodimer, there is a region of CB that is not in contact with CA but exposed to the solvent and able to interact with targets.…”

Section: Discussionmentioning

confidence: 99%

Biophysical studies suggest a new structural arrangement of crotoxin and provide insights into its toxic mechanism

Fernandes

Pazin²,

Dreyer

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Crotoxin (CTX) is the main neurotoxin found in Crotalus durissus rattlesnake venoms being composed by a nontoxic and non-enzymatic component (CA) and a toxic phospholipase A2 (CB). Previous crystallographic structures of CTX and CB provided relevant insights: (i) CTX structure showed a 1:1 molecular ratio between CA and CB, presenting three tryptophan residues in the CA/CB interface and one exposed to solvent; (ii) CB structure displayed a tetrameric conformation. This study aims to provide further information on the CTX mechanism of action by several biophysical methods. Our data show that isolated CB can in fact form tetramers in solution; however, these tetramers can be dissociated by CA titration. Furthermore, CTX exhibits a strong reduction in fluorescence intensity and lifetime compared with isolated CA and CB, suggesting that all tryptophan residues in CTX may be hidden by the CA/CB interface. By companying spectroscopy fluorescence and SAXS data, we obtained a new structural model for the CTX heterodimer in which all tryptophans are located in the interface, and the N-terminal region of CB is largely exposed to the solvent. Based on this model, we propose a toxic mechanism of action for CTX, involving the interaction of N-terminal region of CB with the target before CA dissociation.

show abstract

Section: Discussionmentioning

confidence: 99%

Biophysical studies suggest a new structural arrangement of crotoxin and provide insights into its toxic mechanism

Fernandes

Pazin²,

Dreyer

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…51 Competition experiments suggest that this inhibitor competes with CA for binding to the CB subunit. [52][53][54] The identification of the binding interface in the CA-CB complex determined in this study could help map the binding site of CICS on CB.…”

Section: Discussionmentioning

confidence: 99%

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Faure¹,

Xu²,

Saul³

2011

Journal of Molecular Biology

View full text Add to dashboard Cite

“…This suggestion is based on data showing that antibodies against the C-terminal part of AtxA, a neurotoxin from the Vipera ammodytes ammodytes snake, bind to the C-terminal peptides of CB, protecting mice against the lethal effect potency of CB [ 73 ]. In turn, peptide-array analysis showed that the N-terminal region of CB (Phe11-Ala18) could constitute a pharmacological site of this protein [ 74 ], and chemical modification of Y22 reduced CB neurotoxicity and its binding affinity for presynaptic membranes [ 75 ]. Moreover, the predicted i-face of CB includes several residues from the N-terminal region [ 76 , 77 ].…”

Section: Crotoxin a Heterodimeric Neurotoxin From Crotamentioning

confidence: 99%

Secreted Phospholipases A2 from Animal Venoms in Pain and Analgesia

Zambelli

Picolo

Fernandes

et al. 2017

Toxins

View full text Add to dashboard Cite

Animal venoms comprise a complex mixture of components that affect several biological systems. Based on the high selectivity for their molecular targets, these components are also a rich source of potential therapeutic agents. Among the main components of animal venoms are the secreted phospholipases A2 (sPLA2s). These PLA2 belong to distinct PLA2s groups. For example, snake venom sPLA2s from Elapidae and Viperidae families, the most important families when considering envenomation, belong, respectively, to the IA and IIA/IIB groups, whereas bee venom PLA2 belongs to group III of sPLA2s. It is well known that PLA2, due to its hydrolytic activity on phospholipids, takes part in many pathophysiological processes, including inflammation and pain. Therefore, secreted PLA2s obtained from animal venoms have been widely used as tools to (a) modulate inflammation and pain, uncovering molecular targets that are implicated in the control of inflammatory (including painful) and neurodegenerative diseases; (b) shed light on the pathophysiology of inflammation and pain observed in human envenomation by poisonous animals; and, (c) characterize molecular mechanisms involved in inflammatory diseases. The present review summarizes the knowledge on the nociceptive and antinociceptive actions of sPLA2s from animal venoms, particularly snake venoms.

show abstract

Identification of continuous interaction sites in PLA2-based protein complexes by peptide arrays

Cited by 18 publications

References 37 publications

Biophysical studies suggest a new structural arrangement of crotoxin and provide insights into its toxic mechanism

Biophysical studies suggest a new structural arrangement of crotoxin and provide insights into its toxic mechanism

Crystal Structure of Crotoxin Reveals Key Residues Involved in the Stability and Toxicity of This Potent Heterodimeric β-Neurotoxin

Secreted Phospholipases A2 from Animal Venoms in Pain and Analgesia

Contact Info

Product

Resources

About