Abstract
BackgroundLeishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania. Yet, how META1 contributes to virulence remains unclear. We sought insights into the possible functions of META1 by studying its evolutionary origins.ResultsUsing multiple criteria including sequence similarity, nucleotide composition, phylogenetic analysis and selection pressure on gene sequence, we present evidence that META1 originated in trypanosomatids as a result of a lateral gene transfer of a bacterial heat-inducible protein, HslJ. Furthermore, within the Leishmania genome, META1 sequence is under negative selection pressure against change/substitution. Using homology modeling of Leishmania META1 based on solved NMR structure of HslJ, we show that META1 and HslJ share a similar structural fold. The best hit for other proteins with similar fold is MxiM, a protein involved in the type III secretion system in Shigella. The striking structural similarity shared by META1, HslJ and MxiM suggests a possibility of shared functions. Upon structural superposition with MxiM, we have observed a putative hydrophobic cavity in META1. Mutagenesis of select hydrophobic residues in this cavity affects the secretion of the secreted acid phosphatase (SAP), indicating META1's involvement in secretory processes in Leishmania.ConclusionsOverall, this work uses an evolutionary biology approach, 3D-modeling and site-directed mutagenesis to arrive at new insights into functions of Leishmania META1.
Highlights
Leishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania
The most likely explanation for this unusual phyletic relationship is that META1 in trypanosomatids originated as a result of a lateral gene transfer (LGT) event from bacteria
In order to identify the function of this enigmatic yet essential protein, we have used an evolutionary biology approach to first identify the origins of META1
Summary
Leishmania META1 has for long been a candidate molecule for involvement in virulence: META1 transcript and protein are up-regulated in metacyclic Leishmania. That are differentially expressed in the two META1 was one such gene identified in L. major, found to be conserved across the Leishmania genus. Both transcript and protein was found to be up-regulated in the metacyclic stage of promastigotes. On META1 overexpression in L. amazonensis, parasites were found to be more virulent than wild-type [17] Another gene in Leishmania, up-regulated in metacyclic promastigotes is named META2, and contains three META domains and a calpain-like domain at the carboxy terminus [18]. Apart from some of its developmental expression and its suggested role in virulence, the precise functions of META1 in the parasite remain unknown
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