Synporins--synthetic proteins that emulate the pore structure of biological ionic channels.

Montal, Mauricio; Montal, Myrta S.; Tomich, John M.

doi:10.1073/pnas.87.18.6929

Cited by 108 publications

(56 citation statements)

References 22 publications

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“…species observed with BoTxATM, both in amplitude and in the time that the channels remain open, is anticipated for an amphipathic peptide that self-assembles in the membrane to form noncovalent conductive oligomers of different sizes (Oiki et al, 1988(Oiki et al, , 1990Montal et al, 1990;cf. Montal, 1995).…”

Section: Channel Formation By Botxatmmentioning

confidence: 86%

“…Molecular modeling, energy minimization, and molecular dynamics simulations, were conducted on a Silicon Graphics IRIS 4D/210 GTXB workstation using the INSIGHT and DIS-COVER molecular modeling packages of Biosym (San Diego, California) (Oiki et al, 1990;Montal et al, 1990Montal et al, , 1992. Lowenergy arrangements of a-helices and four-helix bundles were calculated with semiempirical potential energy functions and optimization routines.…”

Section: Con Formational Energy Computationsmentioning

confidence: 99%

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Formation of ion channels in lipid bilayers by a peptide with the predicted transmembrane sequence of botulinum neurotoxin A

et al. 1995

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Synthetic peptides patterned after the predicted transmembrane sequence of botulinum toxin A were used as tools to identify an ion channel-forming motif. A peptide denoted BoTxATM, with the sequence GAVILLEFIPEIAI PVLGTFALV, forms cation-selective channels when reconstituted in planar lipid bilayers. As predicted, the selfassembled conductive oligomers express heterogeneous single-channel conductances. The most frequent openings exhibit single-channel conductance of 12 and 7 pS in 0.5 M NaCI, and 29 and 9 pS in 0.5 M KC1. In contrast, ion channels are not formed by a peptide of the same amino acid composition as BoTxATM with a scrambled sequence. Conformational energy calculations show that a bundle of four amphipathic a-helices is a plausible structural motif underlying the measured pore properties. These studies suggest that the identified module may play a functional role in the ion channel-forming activity of intact botulinum toxin A.

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Section: Channel Formation By Botxatmmentioning

confidence: 86%

Section: Con Formational Energy Computationsmentioning

confidence: 99%

Formation of ion channels in lipid bilayers by a peptide with the predicted transmembrane sequence of botulinum neurotoxin A

et al. 1995

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“…Several synthetic, putative transmembrane segments of natural channel proteins as well as synthetic amphiphilic peptides have been investigated for the purpose of modeling ion channels (Oiki et al, 1988(Oiki et al, , 1990Langosch et al, 1991;Ghosh and Stroud, 1991;Lear et al, 1988;DeGrado and Lear, 1990;Montal et al, 1990). Taking these results and ours into account, it is tempting to suggest that only those peptides which, by molecular modeling, show perfect steric arrangements in the helical bundles, also show defined channel-current fluctuations.…”

Section: Discussionmentioning

confidence: 99%

“…Examples which would fit into this model are the 21-amino-acid peptides composed of repeats of leucines and serines (LSSLLSL),, or an analog with an Aib (a) substitution (LSLaLSL), (Lear et al, 1988;DeGrado and Lear, 1990). On the other hand, synthetic peptides with sequences of the MA segment and the transmembrane M2 segment of the n-AcChoR and the M2 of glycine receptor channels, as well as of the S3 segment of the voltage-gated sodium channel, form channels with variable-conductance states (Oiki et al, 1988;Langosch et al, 1991;Ghosh and Stroud, 1991;Montal et al, 1990). According to the published channel models (Oiki et al, 1990), these peptides do not seem to assemble as perfectly to helix bundles as do those of Lear et al (1988) or ours.…”

Section: Discussionmentioning

confidence: 99%

Structural fluctuations between two conformational states of a transmembrane helical peptide are related to its channel‐forming properties in planar lipid membranes

Vogel

Nilsson

Rigler

et al. 1993

European Journal of Biochemistry

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Putative transmembrane helices of membrane proteins in general and channel proteins in particular often contain proline residues which may induce a bend into an otherwise regular helical structure. Here we show by fluorescence-energy-transfer measurements and molecular-dynamics calculations that, in the case of synthetic bilayer-spanning helical polypeptides, a proline-induced bend in a helix acts as a flexible element mediating rigid body motions of the helical segments. Most important, such structural fluctuations in the transmembrane helices seem to play a functional role in the formation of ionic channels in planar lipid bilayers and biological membranes.Ligand-and voltage-gated channel proteins play a central role in signal-transduction processes across biological membranes (Numa, 1989;Stroud et al., 1990;Galzi et al., 1991;Sakmann, 1992). Unfortunately, there is only a single example where the three-dimensional structure of a channel protein is known at atomic resolution: the recently published structure of the large porin channel of Rhodobacter capsulatus, resolved at 0.18 nm, shows a 16-strand P-sheet barrel arrangement (Weiss et al., 1991). Although similar structural elements were also found within several outer-membrane proteins of Escherichia coli (Engel et al., 1985; Vogel and Jghnig, 1986), the more hydrophobic ligand-and voltagegated channel proteins of higher organisms seem to be composed of domains of different structure (Numa, 1989;Stroud et al., 1990;Galzi et al., 1991). In order to understand the biological function of a channel protein at the molecular level, detailed structural information would be a prerequisite. In spite of the lack of experimental evidence, detailed models have been published of how the polypeptide chains of every membrane-channel protein sequenced are thought to be folded in the lipid bilayer. Based on the pattern of alternating hydrophobic and hydrophilic regions within the amino acid sequence and low-resolution electron-microscopic and Xray-diffraction structural analysis, as well as spectroscopic measurements, models are proposed where the channels are composed of a single protein or of protein subunits containing bundles of membrane-spanning hydrophobic and amphiCorrespondence to H. Vogel, Ecole Polytechnique FBdCrale de

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“…closed times; t,, open times homo-oligomer of five amphipathic a-helices arranged such that polar residues line a central hydrophilic pathway and apolar residues face the hydrophobic bilayer interior [l 11. We have demonstrated that a four-helix bundle protein designated as T,M26, in which four identical helical modules with the sequence of M26 were covalently attached to a multifunctional carrier (template) [25,26], forms ionic channels in lipid bilayers. The T,M26 channel is cation-selective and blocked by mM concentrations of the local anesthetic channel blocker QX-22, properties that are characteristic of the AChR channel [25].…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis and functional characterization of a pentameric channel protein that mimics the presumed pore structure of the nicotinic cholinergic receptor

et al. 1993

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Nicotinic cholinergic receptors are membrane proteins composed of five subunits organized around a central aqueous pore. A pentameric channel protein, T5M2δ, that emulates the presumed pore‐forming structure of this receptor was generated by assembling five helix‐forming peptide modules at the lysine ϵ‐amino groups of the 11‐residue template [K∗AK∗KK∗PGK∗EK∗G], where ∗ indicates attachment sites. Helical modules represent the sequence of the M2 segment of the Torpedo californica acetylcholine receptor (AChR) δ subunit; M2 segments are considered involved in pore‐lining. Purified T5M2δ migrates in SDS‐PAGE with an apparent M r~14,000, concordant with a protein of 126 residues. T5M2δ forms cation‐selective channels when reconstituted in planar lipid bilayers. The single channel conductance in symmetric 0.5 M K.C1 is 40 pS. This value approximates the 45 pS single channel conductance characteristic of authentic purified Torpedo AChR, recorded under otherwise identical conditions. These results, together with conformational energy calculations, support the notion that a bundle of five amphipathic a‐helices is a plausible structural motif underlying the inner bundle that forms the pore of the pentameric AChR channel.

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Synporins--synthetic proteins that emulate the pore structure of biological ionic channels.

Cited by 108 publications

References 22 publications

Formation of ion channels in lipid bilayers by a peptide with the predicted transmembrane sequence of botulinum neurotoxin A

Formation of ion channels in lipid bilayers by a peptide with the predicted transmembrane sequence of botulinum neurotoxin A

Structural fluctuations between two conformational states of a transmembrane helical peptide are related to its channel‐forming properties in planar lipid membranes

Design, synthesis and functional characterization of a pentameric channel protein that mimics the presumed pore structure of the nicotinic cholinergic receptor

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