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Counting charges on membrane-bound peptides.

ABSTRACT: Quantifying the number of charges on peptides bound to interfaces requires reliable estimates of (i) surface coverage and (ii) surface charge, both of which are notoriously difficult parameters to obtain, especially at solid/water interfaces. Here, we report the thermodynamics and electrostatics governing the interactions of l-lysine and l-arginine octamers (Lys₈ and Arg₈) with supported lipid bilayers prepared from a 9?:?1 mixture of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (sodium salt) (DMPG) from second harmonic generation (SHG) spectroscopy, quartz crystal microbalance with dissipation monitoring (QCM-D) and nanoplasmonic sensing (NPS) mass measurements, and atomistic simulations. The combined SHG/QCM-D/NPS approach provides interfacial charge density estimates from mean field theory for the attached peptides that are smaller by a factor of approximately two (0.12 ± 0.03 C m^-2 for Lys₈ and 0.10 ± 0.02 C m^-2 for Arg₈) relative to poly-l-lysine and poly-l-arginine. These results, along with atomistic simulations, indicate that the surface charge density of the supported lipid bilayer is neutralized by the attached cationic peptides. Moreover, the number of charges associated with each attached peptide is commensurate with those found in solution; that is, Lys₈ and Arg₈ are fully ionized when attached to the bilayer. Computer simulations indicate Lys₈ is more likely than Arg₈ to "stand-up" on the surface, interacting with lipid headgroups through one or two sidechains while Arg₈ is more likely to assume a "buried" conformation, interacting with the bilayer through up to six sidechains. Analysis of electrostatic potential and charge distribution from atomistic simulations suggests that the Gouy-Chapman model, which is widely used for mapping surface potential to surface charge, is semi-quantitatively valid; despite considerable orientational preference of interfacial water, the apparent dielectric constant for the interfacial solvent is about 30, due to the thermal fluctuation of the lipid-water interface.

SUBMITTER: McGeachy AC

PROVIDER: S-EPMC5944241 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Counting charges on membrane-bound peptides.

McGeachy Alicia C AC Caudill Emily R ER Liang Dongyue D Cui Qiang Q Pedersen Joel A JA Geiger Franz M FM

Chemical science 20180403 18

Quantifying the number of charges on peptides bound to interfaces requires reliable estimates of (i) surface coverage and (ii) surface charge, both of which are notoriously difficult parameters to obtain, especially at solid/water interfaces. Here, we report the thermodynamics and electrostatics governing the interactions of l-lysine and l-arginine octamers (Lys8 and Arg8) with supported lipid bilayers prepared from a 9 : 1 mixture of 1,2-dimyristoyl-sn-glycero-3-pho ...[more]

PMID: 29780560

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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.

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Counting charges on membrane-bound peptides.

Publications

Counting charges on membrane-bound peptides.

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