Folding Amphipathic Helices Into Membranes: Amphiphilicity Trumps Hydrophobicity

Fernández-Vidal, Mónica; Jayasinghe, Sajith; Ladokhin, Alexey S.; White, Stephen H.

doi:10.1016/j.jmb.2007.05.016

Cited by 159 publications

(157 citation statements)

References 55 publications

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“…The measurements of the interfacial partitioning of a family of 17-residue amidated-acetylated peptides into both neutral and anionic lipid vesicles showed that peptide helicity in water and interface increased linearly with hydrophobic moment, as did the favorable peptide partitioning free energy. This results demonstrates that helical amphipathicity plays more significant roles in interfacial binding than hydrophobicity does (Fernandez-Vidal et al, 2007).…”

Section: Amphipathicity and Hydrophobic Momentmentioning

confidence: 79%

“…Several studies have shown that on the angle of helix content the mean hydrophobic moment is a more important factor affecting antimicrobial activity than hydrophobicity (Pathak et al, 1995;Fernandez-Vidal et al, 2007). The measurements of the interfacial partitioning of a family of 17-residue amidated-acetylated peptides into both neutral and anionic lipid vesicles showed that peptide helicity in water and interface increased linearly with hydrophobic moment, as did the favorable peptide partitioning free energy.…”

Section: Amphipathicity and Hydrophobic Momentmentioning

confidence: 99%

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Alpha-helical cationic antimicrobial peptides: relationships of structure and function

2010

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Antimicrobial peptides (AMPs), with their extraordinary properties, such as broad-spectrum activity, rapid action and difficult development of resistance, have become promising molecules as new antibiotics. Despite their various mechanisms of action, the interaction of AMPs with the bacterial cell membrane is the key step for their mode of action. Moreover, it is generally accepted that the membrane is the primary target of most AMPs, and the interaction between AMPs and eukaryotic cell membranes (causing toxicity to host cells) limits their clinical application. Therefore, researchers are engaged in reforming or de novo designing AMPs as a 'singleedged sword' that contains high antimicrobial activity yet low cytotoxicity against eukaryotic cells. To improve the antimicrobial activity of AMPs, the relationship between the structure and function of AMPs has been rigorously pursued. In this review, we focus on the current knowledge of α-helical cationic antimicrobial peptides, one of the most common types of AMPs in nature.

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Section: Amphipathicity and Hydrophobic Momentmentioning

confidence: 79%

Section: Amphipathicity and Hydrophobic Momentmentioning

confidence: 99%

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

2010

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“…SecY/Sec61 (50), Tom40 (51), and Toc75 (52)). The occurrence and importance of amphipathic helices in membrane proteins have been pointed out previously (53).…”

Section: Discussionmentioning

confidence: 93%

Characterization of Tic110, a Channel-forming Protein at the Inner Envelope Membrane of Chloroplasts, Unveils a Response to Ca2+ and a Stromal Regulatory Disulfide Bridge

Balsera

Goetze

Kovács-Bogdán

et al. 2009

Journal of Biological Chemistry

117

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Tic110 has been proposed to be a channel-forming protein at the inner envelope of chloroplasts whose function is essential for the import of proteins synthesized in the cytosol. Sequence features and topology determination experiments presently summarized suggest that Tic110 consists of six transmembrane helices. Its topology has been mapped by limited proteolysis experiments in combination with mass spectrometric determinations and cysteine modification analysis. Two hydrophobic transmembrane helices located in the N terminus serve as a signal for the localization of the protein to the membrane as shown previously. The other amphipathic transmembrane helices are located in the region composed of residues 92-959 in the pea sequence. This results in two regions in the intermembrane space localized to form supercomplexes with the TOC machinery and to receive the transit peptide of preproteins. A large region also resides in the stroma for interaction with proteins such as molecular chaperones. In addition to characterizing the topology of Tic110, we show that Ca 2؉ has a dramatic effect on channel activity in vitro and that the protein has a redox-active disulfide with the potential to interact with stromal thioredoxin.After the proposed endosymbiotic event that gave rise to chloroplasts and, as a consequence, to the massive transfer of genes from the endosymbiont to the host cell nucleus, two new machineries were developed at the outer and inner envelope of chloroplasts, the TOC and TIC complexes, respectively. The machineries transport plastid proteins, whose synthesis was moved to the cytosol, back to the plastid (for a review, see Refs. 1 and 2). Whereas the channel of the TOC complex is homologous to the Omp85 family of transporters in bacteria (3), the TIC complex shows no homology to known transport systems, since the plasma membrane-bacterial transport machineries were relocated to the thylakoid membrane. Moreover, there was an essential requirement for establishing new lines of communication between the organelle and other parts of the cell (4). In chloroplasts of land plants, redox regulation is linked to oxygen and/or light. The regulation of chloroplast-specific processes by redox in accord with the status of the organelle applies not only for transcription and translation but also for translocation. Redox regulation at the translocation level has been proposed for the TIC machinery on the basis of protein composition and dynamics (5-8) as well as specific in vitro import experiments (9). However, despite advances in our biochemical understanding of the import process, little is presently known regarding details of the role of redox or of the structure of the TIC complex, particularly with respect to its channel subunits.Tic110 is essential for protein import into plastids (10 -12). It has been proposed to be a pore-forming protein and one of the main components of the TIC complex (13). Previous studies have provided information about certain aspects of Tic110 structure-function. The region from residu...

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“…Despite a superficial similarity between pHLIP and amphiphatic peptides, insertion events appear to be driven by different mechanisms. Amphiphatic peptides form ␣-helices on the surfaces of bilayers (25). As with any anisotropic inclusions they occupy only one leaflet of a bilayer and induce distortion, which increases with peptide concentration and finally results in peptide aggregation and cooperative peptide insertion into the membrane, relieving the distortion and accompanied by the formation of a pore (26).…”

Section: (For 37°c) (B)mentioning

confidence: 99%

Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane

Reshetnyak

Andreev

Segala

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

166

180

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The pH low-insertion peptide (pHLIP) serves as a model system for peptide insertion and folding across a lipid bilayer. It has three general states: (I) soluble in water or (II) bound to the surface of a lipid bilayer as an unstructured monomer, and (III) inserted across the bilayer as a monomeric ␣-helix. We used fluorescence spectroscopy and isothermal titration calorimetry to study the interactions of pHLIP with a palmitoyloleoylphosphatidylcholine (POPC) lipid bilayer and to calculate the transition energies between states. We found that the Gibbs free energy of binding to a POPC surface at low pHLIP concentration (state I-state II transition) at 37°C is approximately ؊7 kcal/mol near neutral pH and that the free energy of insertion and folding across a lipid bilayer at low pH (state II-state III transition) is nearly ؊2 kcal/mol. We discuss a number of related thermodynamic parameters from our measurements. Besides its fundamental interest as a model system for the study of membrane protein folding, pHLIP has utility as an agent to target diseased tissues and translocate molecules through the membrane into the cytoplasm of cells in environments with elevated levels of extracellular acidity, as in cancer and inflammation. The results give the amount of energy that might be used to move cargo molecules across a membrane.thermodynamics ͉ drug delivery ͉ imaging ͉ membrane protein T he folding of helical membrane proteins can be conceptualized in terms of distinct steps: (i) peptide insertion and folding to form independently stable helices across a lipid bilayer, (ii) helix association to form a helix bundle intermediate, and (iii) further rearrangements of protein structure and/or binding of prosthetic groups to achieve a functional state (1). Insertion of most membrane proteins is facilitated in vivo by complex molecular machines, such as the translocon, which assist in placing hydrophobic sequences across the bilayer (2). In contrast to more hydrophobic sequences, moderately polar transmembrane domains of Cterminally-anchored proteins can postranslationally translocate themselves into membranes in a translocon-defective yeast strain (3, 4), seeking the free-energy minimum (5). Thus, insertion of a disordered peptide in aqueous solution to form a transbilayer ␣-helix is accompanied by a release of energy, so thermodynamic studies of the interaction of proteins and peptides with a lipid bilayer can provide insights regarding folding. However, such studies are significantly complicated by the poor solubility of membrane peptides, which has made it difficult to separate the contributions of peptide interactions with a lipid bilayer from self-interactions and aggregation.We have been studying a useful system for measurement of the thermodynamics and kinetics of peptide insertion and folding across a lipid bilayer. It is based on the pH low-insertion peptide (pHLIP), which has three major states: (I) soluble in water in an unstructured, monomeric state, (II) bound to the surface of a lipid bilayer in an unstructu...

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Folding Amphipathic Helices Into Membranes: Amphiphilicity Trumps Hydrophobicity

Cited by 159 publications

References 55 publications

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

Alpha-helical cationic antimicrobial peptides: relationships of structure and function

Characterization of Tic110, a Channel-forming Protein at the Inner Envelope Membrane of Chloroplasts, Unveils a Response to Ca2+ and a Stromal Regulatory Disulfide Bridge

Energetics of peptide (pHLIP) binding to and folding across a lipid bilayer membrane

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