The 21‐residue surfactant peptide (LysLeu4)4Lys(KL4) is a transmembrane α‐helix with a mixed nonpolar/polar surface

Gustafsson, Magnus; Vandenbussche, Guy; Curstedt, Tore; Ruysschaert, Jean Marie; Johansson, Jan

doi:10.1016/0014-5793(96)00290-6

Cited by 67 publications

(62 citation statements)

References 29 publications

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“…From studies of a model peptide with basic and hydrophobic residues only, it was suggested that the function of SP-B is to stagger the interfacial phospholipid monolayer via a combination of electrostatic and hydrophobic interactions, and thereby increase the resistance of the monolayer to high surface pressures . This model peptide apparently, however, exhibits a non-amphipathic structure and a transmembranous orientation in a phospholipid environment (Gustafsson et al, 1996), which is in contrast both to the postulated structure of SP-B (Fig. 3) (Anderson et al, 1995a) and to the determined structure and orientation in a lipid bilayer of a synthetic peptide corresponding to positions 1-25 of SP-B (Gordon et al, 1996).…”

Section: Structures Interactions and Dynamics In Relation To Functiomentioning

confidence: 66%

“…KL, was originally designed from structural features observed in the N-terminal part of the SP-B amino acid sequence . Determination of the KL, structure and orientation in Pam,GroPCholPtdGro bilayers however revealed that it is a non-amphipathic transmembrane peptide (Gustafsson et al, 1996) and thus also resembles SP-C. The mechanism of action of KL, and its possible relationships to SP-B (or SP-C), thus remains to be further investigated.…”

Section: Structures Interactions and Dynamics In Relation To Functiomentioning

confidence: 97%

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Molecular Structures and Interactions of Pulmonary Surfactant Components

Johansson

Curstedt

1997

European Journal of Biochemistry

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269

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The dominating functional property of pulmonary surfactant is to reduce the surface tension at the alveolar aidliquid interface, and thereby prevent the lungs from collapsing at the end of expiration. In addition, the system exhibits host-defense properties. Insufficient amounts of pulmonary surfactant in premature infants causes respiratory distress syndrome, a serious threat which nowadays can be effectively treated by airway instillation of surfactant preparations. Surfactant is a mixture of many molecular species, mainly phospholipids and specific proteins, surfactant protein A (SP-A), SP-B, SP-C and SP-D. SP-A and SP-D are water-soluble and belong to the collectins, a family of large multimeric proteins which structurally exhibit collagenousAectin hybrid properties and functionally are Caz+-dependent carbohydrate binding proteins involved in innate host-defence functions. SP-A and SP-D also bind lipids and SP-A is involved in organization of alveolar surfactant phospholipids. SP-B belongs to another family of proteins, which includes also lipid-interacting polypeptides with antibacterial and lytic properties. SP-B is a 17.4-kDa homodimer and each subunit contains three intrachain disulphides and has been proposed to contain four amphipathic helices oriented pairwise in an antiparallel fashion. SP-A, SP-B and SP-D all have been detected also in the gastrointestinal tract. SP-C, in contrast, appears to be a unique protein with extreme structural and stability properties and to exist exclusively in the lungs. SP-C is a lipopeptide containing covalently linked palmitoyl chains and is folded into a 3.7-nm a-helix with a central 2.3-nm all-aliphatic part, making it perfectly suited to interact in a transmembranous way with a fluid bilayer composed of dipalmitoylglycerophosphocholine, the main component of surfactant. Homozygous genetic deficiency of proSP-B causes lethal respiratory distress soon after birth and is associated with aberrant processing of the precursor of SP-C. This review focuses on the chemical composition, structures and interactions of the pulmonary surfactant, in particular the associated proteins.

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Section: Structures Interactions and Dynamics In Relation To Functiomentioning

confidence: 66%

Section: Structures Interactions and Dynamics In Relation To Functiomentioning

confidence: 97%

Molecular Structures and Interactions of Pulmonary Surfactant Components

Johansson

Curstedt

1997

European Journal of Biochemistry

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269

217

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“…However, this peptide behaves more like SP-C than SP-B, and acts as a transmembrane protein at the air-liquid interface. 52,53 The trial by Moya et al 43 compared prophylactic use of lucinactant to beractant and the synthetic surfactant colfosceril palmitate in the rate of RDS at 24 hours and the rate of RDS-related death during the first 14 days after birth. The trial by Sinha et al 42 used a non-inferiority design and compared prophylactic use of lucinactant to poractant alfa in the rate of survival without BPD through 28 days of age.…”

Section: Other Considerationsmentioning

confidence: 99%

Surfactants in the Management of Respiratory Distress Syndrome in Extremely Premature Infants

Ramanathan

2006

The Journal of Pediatric Pharmacology and Therapeutics

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Respiratory distress syndrome (RDS) is primarily due to decreased production of pulmonary surfactant, and it is associated with significant neonatal morbidity and mortality. Exogenous pulmonary surfactant therapy is currently the treatment of choice for RDS, as it demonstrates the best clinical and economic outcomes. Studies confirm the benefits of surfactant therapy to include reductions in mortality, pneumothorax, and pulmonary interstitial emphysema, as well as improvements in oxygenation and an increased rate of survival without bronchopulmonary dysplasia. Phospholipids (PL) and surfactant-associated proteins (SP) play key roles in the physiological activity of surfactant. Different types of natural and synthetic surfactant preparations are currently available. To date, natural surfactants demonstrate superior outcomes compared to the synthetic surfactants, at least during the acute phase of RDS. This disparity is often attributed to biochemical differences including the presence of surfactant-associated proteins in natural products that are not found in the currently available synthetic surfactants. Comparative trials of the natural surfactants strive to establish the precise differences in clinical outcomes among the different preparations. As new surfactants become available, it is important to evaluate them relative to the known benefits of the previously existing surfactants. In order to elucidate the role of surfactant therapy in the management of RDS, it is important to review surfactant biochemistry, pharmacology, and outcomes from randomized clinical trials.

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“…Due to the di¡erences between lipid bilayers and monolayers, it is di¤cult to predict how a transmembrane stretch of 21 residues with charged residues distributed around the helical circumference can be accommodated in a lipid monolayer. No attempt was made in our study to relate the orientation of KL R in a lipid bilayer to the orientation in a lipid monolayer [1]. Further studies are needed in order to establish the orientation of KL R in a lipid monolayer.…”

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et al. 1998

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Our 1996 study [1] was undertaken to characterize the secondary structure and the orientation of the KL R peptide in a lipid environment, and to relate these data to the known structural properties of pulmonary surfactant proteins B and C (SP-B and SP-C).Using polarized Fourier transform infrared (FTIR) spectroscopy and CD spectroscopy we unequivocally demonstrated a helical structure and a transmembrane orientation of KL R in a DPPC/PG bilayer. The monolayer model of KL R proposed by Cochrane and Revak [2] is partly based on £uorescence data [2] and Raman spectroscopy data [3] of the peptide in lipid bilayers. Due to the di¡erences between lipid bilayers and monolayers, it is di¤cult to predict how a transmembrane stretch of 21 residues with charged residues distributed around the helical circumference can be accommodated in a lipid monolayer. No attempt was made in our study to relate the orientation of KL R in a lipid bilayer to the orientation in a lipid monolayer [1]. Further studies are needed in order to establish the orientation of KL R in a lipid monolayer. For example, it has been demonstrated that native SP-C adopts a transmembrane orientation in a lipid bilayer [4,5] but the SP-C helix tilt angle to the interface normal changes from V24³ in lipid bilayers to V70³ in DPPC monolayer ¢lms [6]. We noticed that the orientation of KL R in a lipid bilayer closely resembled that of native SP-C [4^7] but contrasted to the proposed interaction of SP-B with lipid bilayers [8^10], and therefore suggested that the mechanism of action of KL R may be similar to that of SP-C rather than to that of SP-B. We strongly believe that interactions between SP-B, SP-C, and synthetic analogues on the one hand and lipid bilayers on the other are relevant, since these proteins are hydrophobic and need to be transported in a lipid bilayer environment to the interfacial monolayer. It should be remembered that the main location and site of action (bilayer, monolayer, or both) of SP-B and SP-C in lung surfactant remain to be established.We also pointed out that the KL R helix exhibits a mixed nonpolar/polar surface which is di¡erent from the amphipathic SP-B helices [8,11] and nonpolar SP-C helix [12]. The spreading of KL R /DPPC/PG/PA vesicles at an air/water interface is rapid, but slower than the spreading of native SP-C/ DPPC/PG/PA vesicles or vesicles composed of an SP-C/bacteriorhodopsin hybrid mixed with the same lipids [1]. We suggested that this may be caused by the fact that SP-C exhibits à mobility gradient' in a phospholipid bilayer, i.e. only the Nterminal end of the helix contains basic residues that can interact with the phospholipid head groups [7], while KL R is expected to interact similarly with the phospholipid head groups at both ends of the helix [1].Studies of the relationships between structure, orientation and activity of SP-B and SP-C, and their analogues, are necessary in order to understand their roles in the adsorption of phospholipids to the alveolar air-liquid interface. Such knowledge is also requir...

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The 21‐residue surfactant peptide (LysLeu₄)₄Lys(KL₄) is a transmembrane α‐helix with a mixed nonpolar/polar surface

Cited by 67 publications

References 29 publications

Molecular Structures and Interactions of Pulmonary Surfactant Components

Molecular Structures and Interactions of Pulmonary Surfactant Components

Surfactants in the Management of Respiratory Distress Syndrome in Extremely Premature Infants

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