Physical properties and surface activity of surfactant‐like membranes containing the cationic and hydrophobic peptide KL<sub>4</sub>

Sáenz, Alejandra; Cañadas, Olga; Bagatolli, Luís A.; Johnson, Mark E.; Casals, Cristina

doi:10.1111/j.1742-4658.2006.05258.x

Cited by 40 publications

(61 citation statements)

References 45 publications

(87 reference statements)

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“…However, as discussed above, FTIR and CD studies of the structure of KL 4 in lipid environments have led to conflicting results regarding the secondary structure and orientation of KL 4 with respect to a lipid bilayer normal (28-30), possibly due to differences in lipid composition or due to the dependence of these approaches on assumptions regarding secondary structure as well as the solvation status of the peptide backbone. Also, the distribution of the lysines in KL 4 makes its existence as a canonical α-helix on binding to lipids distinctly unfavorable as it would place the charges evenly around the helix rather than making the helix amphipathic (Figure 5).…”

Section: Discussionmentioning

confidence: 99%

“…Some of this divergence between studies may be due to differences in sample preparation and experimental configuration. A recent investigation utilizing CD to study the effect of peptide: lipid ratios and lipid composition on the structure of KL 4 suggests a helical secondary structure is highly dependent on the presence of negatively charged lipids, such as PG, and fluidity of the membrane (30). Unsaturated lipids decrease bilayer packing density and favor the helical conformation.…”

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confidence: 99%

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The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles

et al. 2008

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KL 4 is a 21-residue peptide employed as a functional mimic of lung surfactant protein B which successfully lowers surface tension in the alveoli. A mechanistic understanding of how KL 4 affects lipid properties has proven elusive as the secondary structure of KL 4 in lipid preparations has not been determined at high resolution. The sequence of KL 4 is based on the C-terminus of SP-B, a naturally occurring helical protein that binds to lipid interfaces. The spacing of the lysine residues in KL 4 precludes the formation of a canonical amphipathic α-helix; qualitative measurements using Raman, CDc and FTIR spectroscopies have given conflicting results as to the secondary structure of the peptide as well as its orientation in the lipid environment. Here, we present a structural model of KL 4 bound to lipid bilayers based on solid state NMR data. Double-quantum correlation experiments employing 13 C-enriched peptides were used to quantitatively determine the backbone torsion angles in KL 4 at several positions. These measurements, coupled with CD experiments, verify the helical nature of KL 4 when bound to lipids, with (Φ, Ψ) angles that differ substantially from common values To whom correspondence should be addressed. Tel: 352-846-1506. Fax:352-392-3422. E-mail: jrlong@mbi.ufl for α-helices of (-60, -45). The average torsion angles found for KL 4 bound to POPC: POPG lipid vesicles are (-105, -30); this deviation from ideal α-helical structure allows KL 4 to form an amphipathic helix at the lipid interface.Keywords pulmonary surfactant; Surfactant Protein B; KL 4 ; sinapultide; lucinactant; peptide secondary structure; alpha-helix; hydrophobic moment; lipid bilayers; membrane proteins; phosphatidylcholine; phosphatidylglycerol; solid state NMR; dipolar recoupling; magic angle spinning Pulmonary surfactant is a lipid-rich fluid, containing key proteins, forming the inner mucosal lining of the alveoli. The primary functions of lung surfactant are to minimize surface tension at the alveolar air-fluid interface and provide a barrier against disease (1-5). Inadequate protein levels are a leading cause of respiratory distress syndrome (RDS) in premature infants (6-8).Current therapies for RDS primarily rely on administration of lung surfactant from exogenous sources (9-12). This reliance on xenogenic surfactant is due to the critical role of lung surfactant protein B (SP-B), a highly hydrophobic, 79 residue protein which functions as a homodimer containing 7 disulfide bridges (13). A multitude of roles for SP-B have been proposed and experimentally established. These include surface tension minimization, facilitation of lipid adsorption and resorption at the air-fluid interface, intracellular surfactant trafficking and improved respiratory dynamics in general (14).Synthetic, peptide-based lung surfactant replacements have received noticeable attention (15-17) as the use of synthetic analogs would remove the immunologic risks associated with animal-derived surfactant and allow for greater therapeutic consistency ...

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Section: Discussionmentioning

confidence: 99%

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The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles

et al. 2008

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“…The above clinical trials indicated that Surfaxin forms a gel in its storage form, and must first be heated to 44°C and then shaken before tracheal administration. The physical basis for this gel formation is not yet known, but may be related to the low binding of KL4 to lipids when compared to native SP-B and SP-C [70], and also to the ability of KL4 to form both β-sheet and α-helix with either mixed lipid monolayers [74] or mixed liposomes at high peptide loading [75]. Such stability problems limited the widespread use of Surfaxin in the treatment of surfactant deficiencies, particularly in emergencies, and have led to the voluntary decision by its producer to withdraw Surfaxin from the market in 2015.…”

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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“…Preparation of Phospholipid Vesicles-Multilamellar vesicles (MLVs) and large unilamellar vesicles (LUVs) were prepared as previously described (34). Briefly, different amounts of DPPC, POPC, or POPG, dissolved in chloroform/methanol (3:1) (v/v), were used alone or mixed to achieve the desired ratios.…”

Section: Methodsmentioning

confidence: 99%

Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment

Sáenz

Presto

Lara

et al. 2015

Journal of Biological Chemistry

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Physical properties and surface activity of surfactant‐like membranes containing the cationic and hydrophobic peptide KL₄

Cited by 40 publications

References 45 publications

The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles

The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles

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

Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment

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Physical properties and surface activity of surfactant‐like membranes containing the cationic and hydrophobic peptide KL4

Cited by 40 publications

References 45 publications

The Helical Structure of Surfactant Peptide KL4 When Bound to POPC: POPG Lipid Vesicles

The Helical Structure of Surfactant Peptide KL4 When Bound to POPC: POPG Lipid Vesicles

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

Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment

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Physical properties and surface activity of surfactant‐like membranes containing the cationic and hydrophobic peptide KL₄

The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles

The Helical Structure of Surfactant Peptide KL₄ When Bound to POPC: POPG Lipid Vesicles