Conformations of Signal Peptides Induced by Lipids Suggest Initial Steps in Protein Export

Briggs, Martha S.; Cornell, Donald G.; Dluhy, Richard A.; Gierasch, Lila M.

doi:10.1126/science.2941862

Cited by 226 publications

(118 citation statements)

References 25 publications

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“…These data are consistent with previous studies showing that modulation of the surface pressure of lipid monolayers dictates the ability of signal peptides to intercalate into the acyl chain region (32). Membranes exhibiting rigid gel-phase lipid order are refractory to permeabilization by SHP-1.…”

Section: Discussionsupporting

confidence: 82%

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Harrington

Widener

Stephens

et al. 2010

Journal of Biological Chemistry

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Trypanosoma brucei is the causative agent of both a veterinary wasting disease and human African trypanosomiasis, or sleeping sickness. The cell membrane of the developmental stage found within the mammalian host, the bloodstream form (BSF), is highly dynamic, exhibiting rapid rates of endocytosis and lateral flow of glycosylphosphatidylinositol-anchored proteins. Here, we show that the cell membrane of these organisms is a target for killing by small hydrophobic peptides that increase the rigidity of lipid bilayers. Specifically, we have derived trypanocidal peptides that are based upon the hydrophobic N-terminal signal sequences of human apolipoproteins. These peptides selectively partitioned into the plasma membrane of BSF trypanosomes, resulting in an increase in the rigidity of the bilayer, dramatic changes in cell motility, and subsequent cell death. No killing of the developmental stage found within the insect midgut, the procyclic form, was observed. Additionally, the peptides exhibited no toxicity toward mammalian cell lines and did not induce hemolysis. Studies with model liposomes indicated that bilayer fluidity dictates the susceptibility of membranes to manipulation by hydrophobic peptides. We suggest that the composition of the BSF trypanosome cell membrane confers a high degree of fluidity and unique susceptibility to killing by hydrophobic peptides and is therefore a target for the development of trypanocidal drugs.

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Section: Discussionsupporting

confidence: 82%

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Harrington

Widener

Stephens

et al. 2010

Journal of Biological Chemistry

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“…We utilized a number of assays, including surface tensiometry of peptide-lipid monolayers, to assess the tendency of signal peptides to insert into a lipid phase and to characterize the manner in which they interacted with a lipid monolayer or bilayer. 13,[17][18][19][20][21] Strikingly, functional signal sequences share the capacity to insert spontaneously and deeply into the acyl chain region of a lipid bilayer. Mutations that disrupt the ability to insert into a lipid phase led to loss of targeting function.…”

Section: Signal Peptide Conformations and Membrane Interactionsmentioning

confidence: 99%

Use of synthetic signal sequences to explore the protein export machinery

Clérico¹,

Maki²,

Gierasch³

2008

Biopolymers

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The information for correct localization of newly synthesized proteins in both prokaryotes and eukaryotes resides in self‐contained, often transportable targeting sequences. Of these, signal sequences specify that a protein should be secreted from a cell or incorporated into the cytoplasmic membrane. A central puzzle is presented by the lack of primary structural homology among signal sequences, although they share common features in their sequences. Synthetic signal peptides have enabled a wide range of studies of how these “zipcodes” for protein secretion are decoded and used to target proteins to the protein machinery that facilitates their translocation across and integration into membranes. We review research on how the information in signal sequences enables their passenger proteins to be correctly and efficiently localized. Synthetic signal peptides have made possible binding and crosslinking studies to explore how selectivity is achieved in recognition by the signal sequence‐binding receptors, signal recognition particle, or SRP, which functions in all organisms, and SecA, which functions in prokaryotes and some organelles of prokaryotic origins. While progress has been made, the absence of atomic resolution structures for complexes of signal peptides and their receptors has definitely left many questions to be answered in the future. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90: 307–319, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

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“…Third, the lipid monolayer at the air/water interface will not form aggregates or fuse as happens in the liposome system. Accord-ingly, the monolayer system has been widely applied to studies on the structure and function of biomembrane and lipid/protein interactions (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

The Effects of Protein Hydrophobic Exposure on the Slope of the Line in the Δπ vs πi Plot

Zhang

Wang

et al. 2002

IUBMB Life

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Conformations of Signal Peptides Induced by Lipids Suggest Initial Steps in Protein Export

Cited by 226 publications

References 25 publications

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

The Plasma Membrane of Bloodstream-form African Trypanosomes Confers Susceptibility and Specificity to Killing by Hydrophobic Peptides

Use of synthetic signal sequences to explore the protein export machinery

The Effects of Protein Hydrophobic Exposure on the Slope of the Line in the Δπ vs πi Plot

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