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Novel African trypanocidal agents: membrane rigidifying peptides.

ABSTRACT: The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini coordinate phosphates of the polar lipid headgroups. This mechanism reveals a necessary phenotype in bloodstream form African trypanosomes, high membrane fluidity, and we suggest that targeting the plasma membrane lipid bilayer as a whole may be a novel strategy for the development of new pharmaceutical agents. Additionally, the peptides we have described may be valuable tools for probing the biosynthetic machinery responsible for the unique composition and characteristics of African trypanosome plasma membranes.

SUBMITTER: Harrington JM

PROVIDER: S-EPMC3436892 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Novel African trypanocidal agents: membrane rigidifying peptides.

Harrington John M JM Scelsi Chris C Hartel Andreas A Jones Nicola G NG Engstler Markus M Capewell Paul P MacLeod Annette A Hajduk Stephen S

PloS one 20120907 9

The bloodstream developmental forms of pathogenic African trypanosomes are uniquely susceptible to killing by small hydrophobic peptides. Trypanocidal activity is conferred by peptide hydrophobicity and charge distribution and results from increased rigidity of the plasma membrane. Structural analysis of lipid-associated peptide suggests a mechanism of phospholipid clamping in which an internal hydrophobic bulge anchors the peptide in the membrane and positively charged moieties at the termini c ...[more]

PMID: 22970207

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Project description:The novel neuroproteasome is localized to the neuronal plasma membrane to degrade intracellular proteins into peptides that are released to the extracellular space. Selective inhibition of this neuronal membrane proteasome (NMP) complex ceased the release of peptides and rapidly attenuated neuronal transmission. Based on these findings, we hypothesize that these neuron-specific peptides mediate a novel form of communication through unique peptide-receptor interactions to promote intracellular signaling cascades relevant to neuronal development and function. Our work indicates that NMP peptides can rapidly induce N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx from dendrites to the soma, leading to rapid and sustained phosphorylation of the well-defined activity-dependent transcription factor cAMP response element-binding protein (CREB). We also determined that the gene expression program drastically changes upon NMP peptide treatment of neurons with an increase in expression of immediate early genes (e.g., Fos, Npas4, Egr4) known to have critical neuroregulatory roles. These data support our current thinking that NMP peptides are endogenous and selective activators of synaptic NMDA receptors and are critical for promoting activity-dependent gene expression. This pathway is orthogonal to the classic neurotransmitters previously described to activate NMDARs and points to NMP and its resulting peptides as key contributors to the development and function of the nervous system. However, the unique peptide sequences leading to neuronal activation are still poorly understood. Here, we show that the NMP peptides have tremendous sequence diversity through an unbiased peptidomic approach, and the current ongoing effort is to identify unique active peptide sequences with distinct receptor specificity. Elucidating the mechanism of the NMP and its active peptide products is crucial to understanding the role of this novel signaling process in the nervous system.

Dataset Information

Novel African trypanocidal agents: membrane rigidifying peptides.

Publications

Novel African trypanocidal agents: membrane rigidifying peptides.

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