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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dc.contributor.authorWard, R. J. [UNESP]
dc.contributor.authorRodrigues Alves, A. [UNESP]
dc.contributor.authorRuggiero Neto, J. [UNESP]
dc.contributor.authorArni, R. K. [UNESP]
dc.contributor.authorCasari, G.
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionEMBL
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionLION Bioscience AG
dc.date.accessioned2014-05-27T11:19:34Z
dc.date.available2014-05-27T11:19:34Z
dc.date.issued1998-04-01
dc.description.abstract'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.en
dc.description.affiliationDepartment of Physics IBILCE/UNESP, Sao Jose do Rio Preto-SP
dc.description.affiliationEMBL, Meyerhofstrasse 1, D-96012 Heidelberg
dc.description.affiliationDepartment of Biochemistry FMRP-USP, Avenida Bandeirantes 3900, CEP 14049-900, Ribeirao Preto-SP
dc.description.affiliationLION Bioscience AG, Im Neuenheimer Feld 517, D-69120
dc.description.affiliationUnespDepartment of Physics IBILCE/UNESP, Sao Jose do Rio Preto-SP
dc.format.extent285-294
dc.identifierhttp://dx.doi.org/10.1093/protein/11.4.285
dc.identifier.citationProtein Engineering, v. 11, n. 4, p. 285-294, 1998.
dc.identifier.doi10.1093/protein/11.4.285
dc.identifier.issn0269-2139
dc.identifier.lattes9162508978945887
dc.identifier.orcid0000-0003-2460-1145
dc.identifier.scopus2-s2.0-0031745866
dc.identifier.urihttp://hdl.handle.net/11449/65431
dc.identifier.wosWOS:000074310400005
dc.language.isoeng
dc.relation.ispartofProtein Engineering
dc.rights.accessRightsAcesso restrito
dc.sourceScopus
dc.subjectLys49
dc.subjectMembrane damage
dc.subjectMyotoxicity
dc.subjectPhospholipase A2
dc.subjectSequence analysis
dc.subjectaspartic acid
dc.subjectcalcium ion
dc.subjectlipid
dc.subjectlysine
dc.subjectphospholipase a2
dc.subjectvenom
dc.subjectamino acid sequence
dc.subjectamino acid substitution
dc.subjectcomputer program
dc.subjectgenetic conservation
dc.subjecthuman
dc.subjecthydrolysis
dc.subjectmembrane damage
dc.subjectnonhuman
dc.subjectprediction
dc.subjectpriority journal
dc.subjectAmino Acid Sequence
dc.subjectCell Membrane
dc.subjectLysine
dc.subjectModels, Molecular
dc.subjectMolecular Sequence Data
dc.subjectMuscles
dc.subjectPhospholipases A
dc.subjectSequence Homology, Amino Acid
dc.subjectSnake Venoms
dc.titleA SequenceSpace analysis of Lys49 phospholipases A2: Clues towards identification of residues involved in a novel mechanism of membrane damage and in myotoxicityen
dc.typeArtigo
dcterms.licensehttp://www.oxfordjournals.org/access_purchase/self-archiving_policyb.html
unesp.author.lattes9162508978945887[4]
unesp.author.orcid0000-0003-2460-1145[4]
unesp.campusUniversidade Estadual Paulista (Unesp), Instituto de Biociências Letras e Ciências Exatas, São José do Rio Pretopt

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