New Developments in Liposomal Drug Delivery Pattni, Bhushan S; Chupin, Vladimir V; Torchilin, Vladimir P
Chemical reviews,
10/2015, Letnik:
115, Številka:
19
Journal Article
Recenzirano
Potential applications in the field of liposomal drug delivery are examined. Topics discussed include passive, long-circulating liposomes, active and trigger-based targeting and diseases and route of ...administration.
Growth factor receptor tyrosine kinases of the ErbB family play a significant role in vital cellular processes and various cancers. During signal transduction across plasma membrane, ErbB receptors ...are involved in lateral homodimerization and heterodimerization with proper assembly of their extracellular single-span transmembrane (TM) and cytoplasmic domains. The ErbB1/ErbB2 heterodimer appears to be the strongest and most potent inducer of cellular transformation and mitogenic signaling compared to other ErbB homodimers and heterodimers. Spatial structure of the heterodimeric complex formed by TM domains of ErbB1 and ErbB2 receptors embedded into lipid bicelles was obtained by solution NMR. The ErbB1 and ErbB2 TM domains associate in a right-handed α-helical bundle through their N-terminal double GG4-like motif T
648G
649X
2G
652A
653 and glycine zipper motif T
652X
3S
656X
3G
660, respectively. The described heterodimer conformation is believed to support the juxtamembrane and kinase domain configuration corresponding to the receptor active state. The capability for multiple polar interactions, along with hydrogen bonding between TM segments, correlates with the observed highest affinity of the ErbB1/ErbB2 heterodimer, implying an important contribution of the TM helix–helix interaction to signal transduction.
Proper lateral dimerization of the transmembrane domains of receptor tyrosine kinases is required for biochemical signal transduction across the plasma membrane. The spatial structure of the dimeric ...transmembrane domain of the growth factor receptor ErbB2 embedded into lipid bicelles was obtained by solution NMR, followed by molecular dynamics relaxation in an explicit lipid bilayer. ErbB2 transmembrane segments associate in a right-handed α-helical bundle through the N-terminal tandem GG4-like motif Thr652-X3-Ser656-X3-Gly660, providing an explanation for the pathogenic power of some oncogenic mutations.
We report on an entirely man-made nano-bio architecture fabricated through noncovalent assembly of a cell-free expressed transmembrane proton pump and TiO2 semiconductor nanoparticles as an efficient ...nanophotocatalyst for H2 evolution. The system produces hydrogen at a turnover of about 240 μmol of H2 (μmol protein)−1 h–1 and 17.74 mmol of H2 (μmol protein)−1 h–1 under monochromatic green and white light, respectively, at ambient conditions, in water at neutral pH and room temperature, with methanol as a sacrificial electron donor. Robustness and flexibility of this approach allow for systemic manipulation at the nanoparticle–bio interface toward directed evolution of energy transformation materials and artificial systems.
The choice of a suitable detergent-based membrane mimetic is of crucial importance for high-resolution NMR studies of membrane proteins. The present report describes a new approach of detergent ...screening. It is based on the comparison of 2D 1H,15N-correlation spectra of a protein in a membrane-bilayer “reference” medium and in “trial” detergent-based environments. The proposed “reference” medium is the lipid−protein nanodisc (LPN) representing nanoscale phospholipid bilayers wrapped around by apolipoprotein A-1. The set of zwitterionic (DPC, DMPC/DHPC), anionic (SDS, LMPG, LPPG), and weakly cationic (LDAO) detergent-based media was screened for their ability to represent the native structure of the isolated voltage-sensing domain (VSD) of the archaeal potassium channel KvAP. The VSD/LPN complexes composed of saturated zwitterionic (DMPC), anionic (DMPG), or a mixture of unsaturated differently charged (POPC/DOPG, 3:1) lipids were used as reference. All assayed detergent media demonstrate similar CD spectra of the domain with a high level (∼60%) of overall helicity but different 2D NMR spectra. Using the reference spectrum of the VSD in LPN, we were able to choose the detergent composition in which the membrane-like structure of the VSD is preserved.
Two-component systems (TCS) are widespread signaling systems present in all domains of life. TCS typically consist of a signal receptor/transducer and a response regulator. The receptors (histidine ...kinases, chemoreceptors and photoreceptors) are often embedded in the membrane and have a similar modular structure. Chemoreceptors were shown to function in highly ordered arrays, with trimers of dimers being the smallest functional unit. However, much less is known about photoreceptors. Here, we use small-angle scattering (SAS) to show that detergent-solubilized sensory rhodopsin II in complex with its cognate transducer forms dimers at low salt concentration, which associate into trimers of dimers at higher buffer molarities. We then fit an atomistic model of the whole complex into the SAS data. The obtained results suggest that the trimer of dimers is "tripod"-shaped and that the contacts between the dimers occur only through their cytoplasmic regions, whereas the transmembrane regions remain unconnected.
Title compound was designed to be a black quencher of pyrene fluorescence. It was made amphiphilic to serve as a membrane-bound probe. The synthesis is a two-step procedure. The first step is a ...Mitsunobu reaction of {(phenyldiazenyl)phenyl}diazenylphenol with 1,2-O-isopropylideneglycerol. The second step is the cleavage of the isopropylidene protecting group. The title compound has the extinction coefficient 59,000 at λmax = 380 nm. The Forster distance between the title compound and the pyrene was found to be 37.8 Å.
The structure and dynamics of the isolated voltage-sensing domain (VSD) of the archaeal potassium channel KvAP was studied by high-resolution NMR. The almost complete backbone resonance assignment ...and partial side-chain assignment of the 2H,13C,15N-labeled VSD were obtained for the protein domain solubilized in DPC/LDAO (2:1) mixed micelles. Secondary and tertiary structures of the VSD were characterized using secondary chemical shifts and NOE contacts. These data indicate that the spatial structure of the VSD solubilized in micelles corresponds to the structure of the domain in an open state of the channel. NOE contacts and secondary chemical shifts of amide protons indicate the presence of tightly bound water molecule as well as hydrogen bond formation involving an interhelical salt bridge (Asp62-R133) that stabilizes the overall structure of the domain. The backbone dynamics of the VSD was studied using 15N relaxation measurements. The loop regions S1−S2 and S2−S3 were found mobile, while the S3−S4 loop (voltage-sensor paddle) was found stable at the ps−ns time scale. The moieties of S1, S2, S3, and S4 helices sharing interhelical contacts (at the level of the Asp62-R133 salt bridge) were observed in conformational exchange on the μs−ms time scale. Similar exchange-induced broadening of characteristic resonances was observed for the VSD solubilized in the membrane of lipid−protein nanodiscs composed of DMPC, DMPG, and POPC/DOPG lipids. Apparently, the observed interhelical motions represent an inherent property of the VSD of the KvAP channel and can play an important role in the voltage gating.
In the present Communication we demonstrate the possibility to use high-resolution NMR for the investigation of membrane proteins in reconstituted high-density lipoprotein (rHDL) particles. The rHDL ...particles are nanoscale phospholipid bilayers wrapped around by a dimer of apolipoprotein A-1 (Bayburt, T. H.; Grinkova, Y. V.; Sligar, S. G. Nano Lett. 2002, 2, 853−856). In contrast to the commonly used spherical micelles, the rHDL particles incorporate a lipid bilayer like in biological membranes. These particles still undergo isotropic motion on the NMR time scale, providing the application of high-resolution NMR spectroscopy of the peptides and proteins embedded into their bilayer. As an example, the topology of the membrane-active peptide Antiamoebin-I in the bilayer of the rHDL particles was determined by using the lipid-soluble relaxation probe technique.
Latarcins, linear peptides from the Lachesana tarabaevi spider venom, exhibit a broad-spectrum antimicrobial activity, likely acting on the bacterial cytoplasmic membrane. We study their spatial ...structures and interaction with model membranes by a combination of experimental and theoretical methods to reveal the structure−activity relationship. In this work, a 26 amino acid peptide, Ltc1, was investigated. Its spatial structure in detergent micelles was determined by 1H nuclear magnetic resonance (NMR) and refined by Monte Carlo simulations in an implicit water−octanol slab. The Ltc1 molecule was found to form a straight uninterrupted amphiphilic helix comprising 8–23 residues. A dye-leakage fluorescent assay and 31P NMR spectroscopy established that the peptide does not induce the release of fluorescent marker nor deteriorate the bilayer structure of the membranes. The voltage-clamp technique showed that Ltc1 induces the current fluctuations through planar membranes when the sign of the applied potential coincides with the one across the bacterial inner membrane. This implies that Ltc1 acts on the membranes via a specific mechanism, which is different from the carpet mode demonstrated by another latarcin, Ltc2a, featuring a helix−hinge−helix structure with a hydrophobicity gradient along the peptide chain. In contrast, the hydrophobic surface of the Ltc1 helix is narrow-shaped and extends with no gradient along the axis. We have also disclosed a number of peptides, structurally homologous to Ltc1 and exhibiting similar membrane activity. This indicates that the hydrophobic pattern of the Ltc1 helix and related antimicrobial peptides specifies their activity mechanism. The latter assumes the formation of variable-sized lesions, which depend upon the potential across the membrane.
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