A SequenceSpace analysis of Lys49 phospholipases A2: Clues towards identification of residues involved in a novel mechanism of membrane damage and in myotoxicity

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Data

1998-04-01

Autores

Ward, R. J. [UNESP]
Rodrigues Alves, A. [UNESP]
Ruggiero Neto, J. [UNESP]
Arni, R. K. [UNESP]
Casari, G.

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Resumo

'SequenceSpace' analysis is a novel approach which has been used to identify unique amino acids within a subfamily of phospholipases A2 (PLA2) in which the highly conserved active site residue Asp49 is substituted by Lys (Lys49-PLA2s). Although Lys49-PLA2s do not bind the catalytic co-factor Ca2+ and possess extremely low catalytic activity, they demonstrate a Ca2+-independent membrane damaging activity through a poorly understood mechanism, which does not involve lipid hydrolysis. Additionally, Lys49-PLA2s possess combined myotoxic, oedema forming and cardiotoxic pharmacological activities, however the structural basis of these varied functions is largely unknown. Using the 'SequenceSpace' analysis we have identified nine residues highly unique to the Lys49-PLA2 sub-family, which are grouped in three amino acid clusters in the active site, hydrophobic substrate binding channel and homodimer interface regions. These three highly specific residue clusters may have relevance for the Ca2+-independent membrane damaging activity. Of a further 15 less stringently conserved residues, nine are located in two additional clusters which are well isolated from the active site region. The less strictly conserved clusters have been used in predictive sequence searches to correlate amino acid patterns in other venom PLA2s with their pharmacological activities, and motifs for presynaptic and combined toxicities are proposed.

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Palavras-chave

Lys49, Membrane damage, Myotoxicity, Phospholipase A2, Sequence analysis, aspartic acid, calcium ion, lipid, lysine, phospholipase a2, venom, amino acid sequence, amino acid substitution, computer program, genetic conservation, human, hydrolysis, membrane damage, nonhuman, prediction, priority journal, Amino Acid Sequence, Cell Membrane, Lysine, Models, Molecular, Molecular Sequence Data, Muscles, Phospholipases A, Sequence Homology, Amino Acid, Snake Venoms

Como citar

Protein Engineering, v. 11, n. 4, p. 285-294, 1998.