The relationship between compositional phase separation and vesicle morphology: Implications for the regulation of phospholipase A2 by membrane structure

Burack, W. Richard; Dibble, Andrew R. G.; Biltonen, Rodney L.

doi:10.1016/s0009-3084(97)00084-4

Cited by 16 publications

(10 citation statements)

References 20 publications

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“…Since the end of the lag time correlates with the formation of Cer-enriched domains, as described previously [8,28], the initial presence of laterally segregated domains may explain the shortening of SMase precatalytic steps, evidenced as a shortening of the lag time period, perhaps increasing the local enzyme concentration at boundary defects due to the lateral interfaces. The presence of surface defects due to phase coexistence, has long been known to activate various phospholipases [12,24,[37][38][39][40].…”

Section: Resultsmentioning

confidence: 99%

The initial surface composition and topography modulate sphingomyelinase-driven sphingomyelin to ceramide conversion in lipid monolayers

Tullio

Maggio

Härtel

et al. 2007

Cell Biochem Biophys

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Changes of the initial composition and topography of mixed monolayers of Sphingomyelin and Ceramide modulate the degradation of Sphingomyelin by Bacillus cereus Sphingomyelinase. The presence of initial lateral phase boundary due to coexisting condensed and expanded phase domains favors the precatalytic steps of the reaction. The amount and quality of the domain lateral interface, defined by the type of boundary undulation, appears as a modulatory supramolecular code which regulates the catalytic efficiency of the enzyme. The long range domain lattice structuring is determined by the Sphingomyelinase activity.

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Section: Resultsmentioning

confidence: 99%

The initial surface composition and topography modulate sphingomyelinase-driven sphingomyelin to ceramide conversion in lipid monolayers

Tullio

Maggio

Härtel

et al. 2007

Cell Biochem Biophys

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“…A question therefore arises as to the precise mechanism of the deactivation of the PLA 2 and its subsequent reactivation by the a-amylase. Several groups have shown that PLA 2 hydrolysis occurs at the interface between phospholipid structures and an aqueous phase, [8] selectively cleaving the sn-2 acyl chain in 1,2-diacyl-sn-phospholipids [9] and generating a fatty acid and a lyso-phospholipid, leading to a loss of structural integrity of the membrane, [10,11] a reduction in the liposome size [12] and the formation of smaller self-assembled structures such as micelles [13] and disks [14] . Elegant reflectivity studies have quantified the effect of phospholipid structure on the level of PLA 2 adsorption at and depth of penetration into the monolayer, the subsequent rate of phospholipid degradation, [15] and have also demonstrated that the fatty acid accumulates in the membrane whereas the lysophospholipid forms micelles in solution, [16] leading to the suggestion that PLA 2 becomes preferentially solubilized into these domains, leading to its inactivation.…”

Section: Introductionmentioning

confidence: 99%

Time‐Resolved Small‐Angle Neutron Scattering as a Tool for Studying Controlled Release from Liposomes using Polymer‐Enzyme Conjugates

Ferguson¹,

Luca²,

Heenan³

et al. 2010

Macromol. Rapid Commun.

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The action of phospholipase A2 (PLA2) on 1,2‐dipalmitoyl‐sn‐glycero‐3‐phosphocholine (DPPC) liposomes (vesicles) – an integral component in the polymer enzyme liposome therapy (PELT) mechanism (R. Duncan et al., J. Controlled Release 2001, 74, 135) for the controlled delivery of poorly soluble therapeutic molecules within liposomes – may be “masked” by conjugation to the biodegradable polymer dextrin and subsequently regenerated by the endogenous enzyme α‐amylase that degrades the dextrin; that is, incorporating the so‐called polymer‐unmasked‐masked protein therapy (PUMPT) approach (R. Duncan, et al. Biomacromolecules 2008, 9, 1146). Small‐angle neutron scattering (SANS) has been used to quantify the detailed structure of DPPC liposomes and any perturbation in that structure induced by the presence of PLA2 in native, “masked” (dextrin–PLA2 conjugate) and an in situ α‐amylase‐unmasked form. A time‐dependent degradation of the vesicular structure was observed for the two active PLA2 cases, but not for the masked case. This study demonstrates that the PLA2‐induced hydrolysis of the DPPC – and the associated rupture of the liposome and the release of the enclosed material – may be controlled through masking with dextrin. Accordingly, the viability of using such a combinatorial nanomedicine approach as a general route for the controlled delivery of poorly soluble therapeutic molecules is shown.magnified image

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“…In the case of small unilamellar vesicles the enzyme shows sensitivity to different degrees of curvature (Bell and Biltonen, 1989). Furthermore, the enzyme has also been postulated to present increased sensitivity toward regions of high curvature achieved by product accumulation and phase separation (Burack and Biltonen, 1994;Burack et al, 1997b). Large unilamellar vesicles show under certain conditions a so-called lag-burst behavior where a long lag time of low activity is followed by a period of rapid hydrolysis (Apitz-Castro et al, 1982;Hønger et al, 1996;Nielsen et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Evolution of a Rippled Membrane during Phospholipase A2 Hydrolysis Studied by Time-Resolved AFM

Leidy

Mouritsen

Jørgensen

et al. 2004

Biophysical Journal

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The sensitivity of phospholipase A(2) (PLA(2)) for lipid membrane curvature is explored by monitoring, through time-resolved atomic force microscopy, the hydrolysis of supported double bilayers in the ripple phase. The ripple phase presents a corrugated morphology. PLA(2) is shown to have higher activity toward the ripple phase compared to the gel phase in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) membranes, indicating its preference for this highly curved membrane morphology. Hydrolysis of the stable and metastable ripple structures is monitored for equimolar DMPC/1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)-supported double bilayers. As shown by high-performance liquid chromatography results, DSPC is resistant to hydrolysis at this temperature, resulting in a more gradual hydrolysis of the surface that leads to a change in membrane morphology without loss of membrane integrity. This is reflected in an increase in ripple spacing, followed by a sudden flattening of the lipid membrane during hydrolysis. Hydrolysis of the ripple phase results in anisotropic holes running parallel to the ripples, suggesting that the ripple phase has strip regions of higher sensitivity to enzymatic attack. Bulk high-performance liquid chromatography measurements indicate that PLA(2) preferentially hydrolyzes DMPC in the DMPC/DSPC ripples. We suggest that this leads to the formation of a flat gel-phase lipid membrane due to enrichment in DSPC. The results point to the ability of PLA(2) for inducing a compositional phase transition in multicomponent membranes through preferential hydrolysis while preserving membrane integrity.

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The relationship between compositional phase separation and vesicle morphology: Implications for the regulation of phospholipase A2 by membrane structure

Cited by 16 publications

References 20 publications

The initial surface composition and topography modulate sphingomyelinase-driven sphingomyelin to ceramide conversion in lipid monolayers

The initial surface composition and topography modulate sphingomyelinase-driven sphingomyelin to ceramide conversion in lipid monolayers

Time‐Resolved Small‐Angle Neutron Scattering as a Tool for Studying Controlled Release from Liposomes using Polymer‐Enzyme Conjugates

Evolution of a Rippled Membrane during Phospholipase A2 Hydrolysis Studied by Time-Resolved AFM

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