The influence of cholesterol on melittin lipidation in neutral membranes

Britt, Hannah M.; Mosely, Jackie A.; Sanderson, John M.

doi:10.1039/c8cp06661b

Cited by 7 publications

(17 citation statements)

References 69 publications

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“…Our work with melittin indicates that penetration depth is the more significant of the two factors in determining the rate at which lipidation occurs. [7] As a whole, these data indicate the there is a very real potential for small changes in cholesterol levels or lipid composition to place suitable A residues in a position to undergo intrinsic lipidation. Consistent with this notion, NMR studies using 13 C labeled amino acids incorporated into synthetic peptides suggest that Asp23 and Ser26 are close to lipid methylene groups.…”

Section: Box 1: the Role Of Membranes In A Fibrillogenesismentioning

confidence: 84%

“…When 20 mol% cholesterol is included in POPC membranes, more than 50% of the melittin sample is lipidated within 24 h, despite melittin having a lower binding affinity for these membranes. The presence of cholesterol also changes the relative selectivity of N‐terminal versus Lys23 lipidation in comparison to the same system without cholesterol …”

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

“…Lipidation reactions have been described in most detail for the peptide melittin using liposomes as a membrane model. [7,9,10] Other peptides are known to be reactive, including magainin II, penetratin, and PGLa. [8] Typically, the sites to which acyl transfer occurs include the N-terminal amino group, the -amino group of lysine, and the hydroxyl group of serine.…”

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

“…The presence of cholesterol also changes the relative selectivity of N-terminal versus Lys23 lipidation in comparison to the same system without cholesterol. [7] To date, studies of peptide lipidation have been conducted in vitro using liposomes as model systems. Liposomes offer the advantage of enabling conditions to be precisely controlled and systematically varied, without the complications that arise from the presence of other potential acyl donors, such as acyl CoA derivatives.…”

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

“…Lipids that have ester-linked fatty acyl chains, such as diacylglycerophospholipids, have a surprisingly high intrinsic susceptibility toward lytic reactions involving nucleophilic attack at the carbonyl group. Both the catalysis of lipid hydrolysis by non-lipid components, leading to the formation of fatty acids and lysolipids (Figure 1), [4][5][6] and direct reactivity leading to fatty acyl group transfer from the lipid to the non-lipid component DOI: 10.1002/bies.201900147 (i.e., a lipidation reaction), also with the concomitant formation of a lysolipid, [4,[7][8][9][10] have been described. The term "intrinsic lipidation" is used to describe this direct acyl transfer from a membrane lipid as the donor to a membrane-associated acceptor molecule.…”

Section: Introductionmentioning

confidence: 99%

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Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Sanderson

2020

BioEssays

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In this article, it is hypothesized that a fundamental chemical reactivity exists between some non‐lipid constituents of cellular membranes and ester‐based lipids, the significance of which is not generally recognized. Many peptides and smaller organic molecules have now been shown to undergo lipidation reactions in model membranes in circumstances where direct reaction with the lipid is the only viable route for acyl transfer. Crucially, drugs like propranolol are lipidated in vivo with product profiles that are comparable to those produced in vitro. Some compounds have also been found to promote lipid hydrolysis. Drugs with high lytic activity in vivo tend to have higher toxicity in vitro. Deacylases and lipases are proposed as key enzymes that protect cells against the effects of intrinsic lipidation. The toxic effects of intrinsic lipidation are hypothesized to include a route by which nucleation can occur during the formation of amyloid fibrils.

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Section: Box 1: the Role Of Membranes In A Fibrillogenesismentioning

confidence: 84%

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

Section: Lipidation Reactions Have Been Modeled In Vitro and Detectedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Sanderson

2020

BioEssays

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Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation

et al. 2023

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Huntington's disease (HD) is a neurodegenerative disease resulting from an expansion of the polyglutamine (polyQ) domain within the huntingtin protein (htt). PolyQ expansion triggers toxic aggregation and alters htt/lipid interactions. The first 17 amino acids at the N‐terminus of htt (Nt17) have a propensity to form an amphipathic α‐helix crucial to aggregation and membrane binding. Htt interacts closely with a variety of membrane systems including those of the endoplasmic reticulum, mitochondria, nuclear envelope, and plasma membrane. Membrane composition heavily influences both htt aggregation and lipid interactions, and cholesterol is a crucial membrane component that modulates properties such as fluidity, permeability, and organization. In HD, cholesterol homeostasis is disrupted, and likely plays a role in toxicity. The objective of these studies was to identify the impact of cholesterol on htt aggregation and lipid interactions in various lipid systems. Lipid systems of POPC, DOPC, and POPG with varied levels of exogenously added cholesterol were exposed to htt, and the influences on aggregation, lipid binding, and htt/lipid complexation were evaluated using thioflavin‐T aggregation assays, atomic force microscopy, colorimetric lipid binding assays, and mass spectrometry. The addition of cholesterol to DOPC vesicles enhanced htt aggregation. In the presence of vesicles of either POPC or POPG, the addition of cholesterol reduced htt aggregation. Htt/lipid binding decreased for POPC and increased for both DOPC and POPG with increasing cholesterol content, with observed differences in htt/lipid complexation. Altered cholesterol content influences htt aggregation, lipid binding, and complexation differently depending on overall lipid composition.

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Design of a hybrid peptide derived from Melittin and CXCL14 –C17: A molecular dynamics simulation study

et al. 2022

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The influence of cholesterol on melittin lipidation in neutral membranes

Abstract: Cholesterol inclusion in membranes influences the rate and selectivity of acyl transfer from lipids to a membrane-embedded peptide.

Cited by 7 publications

References 69 publications

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Far from Inert: Membrane Lipids Possess Intrinsic Reactivity That Has Consequences for Cell Biology

Cholesterol impacts the formation of huntingtin/lipid complexes and subsequent aggregation

Design of a hybrid peptide derived from Melittin and CXCL14 –C17: A molecular dynamics simulation study

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