Structure of Mini-B, a Functional Fragment of Surfactant Protein B, in Detergent Micelles<sup>,</sup>

Sarker, Muzaddid; Waring, Alan J.; Walther, Frans J.; Keough, K. M. W.; Booth, Valerie

doi:10.1021/bi7011756

Cited by 53 publications

(67 citation statements)

References 59 publications

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“…Our working hypothesis is that the SP-Css ion-lock 1 in lipids improves its surfactant functions by stabilizing α -helix through a close-range salt-bridge between the Glu − -20 and Lys + -24 residues. As a further test of this proposition, more detailed 3D information on the structure and membrane topography of SP-C ion-locks will be obtained using 13 C-FTIR spectroscopy (Gordon et al, 2000; Waring et al, 2005), 2D-NMR spectrometry (Sarker et al, 2007) and/or all-atom MD simulation techniques (Walther et al, 2010; Almlen et al, 2010). Additionally, polarized FTIR spectra of SP-C mimics in surfactant lipids should indicate the fatty-acyl chain orientation with respect to the peptide helical axis, and likewise show if there are any protein-induced perturbations in lipid conformations (Clercx et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Walther

Waring

Hernández-Juviel

et al. 2014

PeerJ

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Background. Surfactant protein C (SP-C; 35 residues) in lungs has a cationic N-terminal domain with two cysteines covalently linked to palmitoyls and a C-terminal region enriched in Val, Leu and Ile. Native SP-C shows high surface activity, due to SP-C inserting in the bilayer with its cationic N-terminus binding to the polar headgroup and its hydrophobic C-terminus embedded as a tilted, transmembrane α-helix. The palmitoylcysteines in SP-C act as ‘helical adjuvants’ to maintain activity by overriding the β-sheet propensities of the native sequences.Objective. We studied SP-C peptides lacking palmitoyls, but containing glutamate and lysine at 4-residue intervals, to assess whether SP-C peptides with salt-bridges (“ion-locks”) promote surface activity by mimicking the α-helix and membrane topography of native SP-C.Methods. SP-C mimics were synthesized that reproduce native sequences, but without palmitoyls (i.e., SP-Css or SP-Cff, with serines or phenylalanines replacing the two cysteines). Ion-lock SP-C molecules were prepared by incorporating single or double Glu−–Lys+ into the parent SP-C’s. The secondary structures of SP-C mimics were studied with Fourier transform infrared (FTIR) spectroscopy and PASTA, an algorithm that predicts β-sheet propensities based on the energies of the various β-sheet pairings. The membrane topography of SP-C mimics was investigated with orientated and hydrogen/deuterium (H/D) exchange FTIR, and also Membrane Protein Explorer (MPEx) hydropathy analysis. In vitro surface activity was determined using adsorption surface pressure isotherms and captive bubble surfactometry, and in vivo surface activity from lung function measures in a rabbit model of surfactant deficiency.Results. PASTA calculations predicted that the SP-Css and SP-Cff peptides should each form parallel β-sheet aggregates, with FTIR spectroscopy confirming high parallel β-sheet with ‘amyloid-like’ properties. The enhanced β-sheet properties for SP-Css and SP-Cff are likely responsible for their low surfactant activities in the in vitro and in vivo assays. Although standard 12C-FTIR study showed that the α-helicity of these SP-C sequences in lipids was uniformly increased with Glu−–Lys+ insertions, elevated surfactant activity was only selectively observed. Additional results from oriented and H/D exchange FTIR experiments indicated that the high surfactant activities depend on the SP-C ion-locks recapitulating both the α-helicity and the membrane topography of native SP-C. SP-Css ion-lock 1, an SP-Css with a salt-bridge for a Glu−–Lys+ ion-pair predicted from MPEx hydropathy calculations, demonstrated enhanced surfactant activity and a transmembrane helix simulating those of native SP-C.Conclusion. Highly active SP-C mimics were developed that replace the palmitoyls of SP-C with intrapeptide salt-bridges and represent a new class of synthetic surfactants with therapeutic interest.

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Section: Discussionmentioning

confidence: 99%

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Walther

Waring

Hernández-Juviel

et al. 2014

PeerJ

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“…Mini-B has been shown to retain certain activity of the full-length SP-B. 54 Two tails of the SP-C peptide (PDB ID: 1SPF) has been palmitoylated, which is crucial for its surface activity. 55 The complete molecular structure of the hydrophilic surfactant protein SP-A is not yet available.…”

Section: Methodsmentioning

confidence: 99%

Unveiling the Molecular Structure of Pulmonary Surfactant Corona on Nanoparticles

et al. 2017

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The growing risk of human exposure to airborne nanoparticles (NPs) causes a general concern on the biosafety of nanotechnology. Inhaled NPs can deposit in the deep lung at which they interact with the pulmonary surfactant (PS). Despite the increasing study of nano-bio interactions, detailed molecular mechanisms by which inhaled NPs interact with the natural PS system remain unclear. Using coarse-grained molecular dynamics simulation, we studied the interaction between NPs and the PS system in the alveolar fluid. It was found that regardless of different physicochemical properties, upon contacting the PS, both silver and polystyrene NPs are immediately coated with a biomolecular corona that consists of both lipids and proteins. Structure and molecular conformation of the PS corona depend on the hydrophobicity of the pristine NPs. Quantitative analysis revealed that lipid composition of the corona formed on different NPs is relatively conserved and is similar to that of the bulk phase PS. However, relative abundance of the surfactant-associated proteins, SP-A, SP-B, and SP-C, is notably affected by the hydrophobicity of the NP. The PS corona provides the NPs with a physicochemical barrier against the environment, equalizes the hydrophobicity of the pristine NPs, and may enhance biorecognition of the NPs. These modifications in physicochemical properties may play a crucial role in affecting the biological identity of the NPs and hence alter their subsequent interactions with cells and other biological entities. Our results suggest that all studies of inhalation nanotoxicology or NP-based pulmonary drug delivery should consider the influence of the PS corona.

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“…More recently, 2D-NMR spectroscopy has elucidated the 3-D structure of reduced MB in an HFIP solution, and that of oxidized MB in sodium dodecyl sulfate (SDS) detergent micelles [21]. Similar to that noted above for oxidized MB (1SSZ) in HFIP, 2D-NMR analysis showed that the N- and C-terminal regions of reduced MB in HFIP (PDB: 2JOU) fold as α-helices (Figures 3A and 3B).…”

Section: Mini-b (Mb) and Super Mini-b (S-mb) Synthetic Peptidesmentioning

confidence: 99%

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

2016

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Surfactant protein (SP)-B is a 79-residue polypeptide crucial for the biophysical and physiological function of endogenous lung surfactant. SP-B is a member of the saposin or saposin-like proteins (SAPLIP) family of proteins that share an overall three-dimensional folding pattern based on secondary structures and disulfide connectivity and exhibit a wide diversity of biological functions. Here, we review the synthesis, molecular biophysics and activity of synthetic analogs of saposin proteins designed to mimic those interactions of the parent proteins with lipids that enhance interfacial activity. Saposin proteins generally interact with target lipids as either monomers or multimers via well-defined amphipathic helices, flexible hinge domains, and insertion sequences. Based on the known 3D-structural motif for the saposin family, we show how bioengineering techniques may be used to develop minimal peptide constructs that maintain desirable structural properties and activities in biomedical applications. One important application is the molecular design, synthesis and activity of Saposin mimics based on the SP-B structure. Synthetic lung surfactants containing active SP-B analogs may be potentially useful in treating diseases of surfactant deficiency or dysfunction including the neonatal respiratory distress syndrome and acute lung injury/acute respiratory distress syndrome.

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Structure of Mini-B, a Functional Fragment of Surfactant Protein B, in Detergent Micelles^,

Cited by 53 publications

References 59 publications

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Unveiling the Molecular Structure of Pulmonary Surfactant Corona on Nanoparticles

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

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Structure of Mini-B, a Functional Fragment of Surfactant Protein B, in Detergent Micelles,

Cited by 53 publications

References 59 publications

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Surfactant protein C peptides with salt-bridges (“ion-locks”) promote high surfactant activities by mimicking theα-helix and membrane topography of the native protein

Unveiling the Molecular Structure of Pulmonary Surfactant Corona on Nanoparticles

Design of Surfactant Protein B Peptide Mimics Based on the Saposin Fold for Synthetic Lung Surfactants

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Structure of Mini-B, a Functional Fragment of Surfactant Protein B, in Detergent Micelles^,