Sphingomyelin Stereoisomers Reveal That Homophilic Interactions Cause Nanodomain Formation

Yano, Yo; Hanashima, Shinya; Yasuda, Tomokazu; Tsuchikawa, Hiroshi; Matsumori, Nobuaki; Kinoshita, Masanao; Sazzad, Abdullah Al; Slotte, J. Peter; Murata, Michio

doi:10.1016/j.bpj.2019.03.031

Cited by 6 publications

(32 citation statements)

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“…The lateral packing of L‐ threo ‐SM, which occurs as a common impurity in semisynthetic SMs, is slightly weaker than that of natural SM; by differential scanning calorimetry (DSC), L‐ threo SM with a stearoyl chain exhibited a slightly lower main phase transition temperature ( T m ; 44.1‐44.2°C) as compared with that of native SM ( T m ; 44.7‐44.9°C) (Figure ) . These data suggested that compared with the L‐ threo configuration, the D‐ erythro configuration plays a certain role in the stabilization of SM‐SM interactions via appropriate hydrogen bonding.…”

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 98%

“…Differential scanning calorimetry thermograms of native stearoyl sphingomyelin (SM) (A); its enantiomer, ent‐ SM (B); and diastereomer, threo‐ SM (C) . Reprinted with permission from Biophysical Journal, 2018, 115, 1530‐1540.…”

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

“…When the chiral moiety is involved in interactions with other chiral molecules, detectable differences usually appear between enantiomers. Actually, stearoyl ent ‐SM, which is chemically synthesized from D‐serine, exhibits T m (45.0°C) almost identical to that of natural D‐ erythro SM by DSC . When mixing both enantiomers to form a “racemic” bilayer membrane, it is intriguing whether the chiral resolution via stereoselective homophilic interactions occurs to separately form the native SM domain and ent‐ SM domain.…”

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

“…Therefore, pseudo‐racemic bilayers are prepared by the mixing of stearoyl ent‐ SM with palmitoyl SM ( T m ; 41°C) . The mixed membrane of two lipids with different melting temperatures exhibited two endothermic peaks at 41.9 and 42.4°C (Figure B), respectively; thus, ent‐ SM can be segregated from native SMs. In contrast, a pair of phosphatidylcholine (PC) having an sn‐2 palmitoyl or a stearoyl chain did not exhibit separate peaks in the DSC thermogram, indicating that the two PCs are well mixed in the gel phase (Figure D).…”

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

“…Palmitoyl‐SM (PSM)/SSM (A) and PSM‐ ent‐ SSM (B) exhibited different melting behaviors. In contrast, palmitoyl‐stearoyl‐PC (PSPC)/DPPC (C) and PSPC/ ent‐ DPPC (D) exhibited similar endothermal patterns . Results were previously published, while thermograms in panels (C) and (D) were obtained from newly conducted experiments.…”

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

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Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

2020

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Most phospholipids constituting biological membranes are chiral molecules with a hydrophilic head group and hydrophobic alkyl chains, rendering biphasic property characteristic of membrane lipids. Some lipids assemble into small domains via chirality‐dependent homophilic and heterophilic interactions, the latter of which sometimes include cholesterol to form lipid rafts and other microdomains. On the other hand, lipid mediators and hormones derived from chiral lipids are recognized by specific membrane or nuclear receptors to induce downstream signaling. It is crucial to clarify the physicochemical properties of the lipid self‐assembly for the study of the functions and behavior of biological membranes, which often become elusive due to effects of membrane proteins and other biological events. Three major lipids with different skeletal structures were discussed: sphingolipids including ceramides, phosphoglycerolipids, and cholesterol. The physicochemical properties of membranes and physiological functions of lipid enantiomers and diastereomers were described in comparison to natural lipids. When each enantiomer formed a self‐assembly or interacted with achiral lipids, both lipid enantiomers exhibited identical membrane physicochemical properties, while when the enantiomer interacted with chiral lipids or with the opposite enantiomer, mixed membranes exhibited different properties. For example, racemic membranes comprising native sphingomyelin and its antipode exhibited phase segregation due to their strong homophilic interactions. Therefore, lipid enantiomers and diastereomers can be good probes to investigate stereospecific lipid‐lipid and lipid‐protein interactions occurring in biological membranes.

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Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 98%

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

Section: Sphingomyelin Diastereomers and Enantiomermentioning

confidence: 99%

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Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

2020

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Cholesterol-Induced Conformational Change in the Sphingomyelin Headgroup

Hanashima

Murakami

Yura

et al. 2019

Biophysical Journal

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Sphingomyelin (SM) and cholesterol (Cho) are the important lipids for the formation of biologically functional membrane domains, lipid rafts. However, the interaction between Cho and the headgroup of SM remains unclear. In this study, we performed solid-state NMR experiments to reveal the Cho effects on the headgroup conformation using 2 H-labeled stearoyl-SM (SSM). Deuterated SSMs at the Ca, Cb, and Cg positions of a choline moiety were separately prepared and subjected to NMR measurements to determine the quadrupolar splitting of 2 H signals in hydrated SSM unitary and SSM/Cho (1:1) bilayers. Using 2 H NMR and 13 C-31 P REDOR data, the conformation and orientation of the choline moiety were deduced and compared with those derived from molecular dynamics simulations. In SSM unitary bilayers, three torsional angles in the phosphocholine moiety, P-O-Ca-Cb, were found to be consecutive þgauche(g)/þg/þg or Àg/Àg/Àg. The orientation and conformation of the SSM headgroup were consistent with the results of our molecular dynamics simulations and the previous results on phosphatidylcholines. The quadrupolar coupling at the a methylene group slightly increased in the presence of Cho, and those at the Cb and Cg decreased more significantly, thus suggesting that Cho reduced the gauche conformation at the Ca-Cb torsion. The conformational ensemble in the presence of Cho may enhance the so-called umbrella effect of the SSM headgroup, resulting in the stabilization of Cho near the SM molecules by concealing the hydrophobic Cho core from interfacial water. We also examined the effect of the chiral centers at the sphingosine chain to the headgroup conformation by determining the enantiomeric excess between the diastereomeric þg/þg/þg and Àg/Àg/Àg conformers using (S)-Ca-deuterated and (R)-Ca-deuterated SSMs. Their 2 H NMR measurements showed that the chiral centers induced the slight diastereomeric excess in the SM headgroup conformation.

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Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

Yano

Hanashima

Tsuchikawa

et al. 2020

Biophysical Journal

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Sphingomyelin (SM), a major component of small domains (or lipid rafts) in mammalian cell membranes, forms a liquid-ordered phase in the presence of cholesterol (Cho). However, the nature of molecular interactions within the ordered SM/Cho phase remains elusive. We previously revealed that stearoyl-SM (SSM) and its enantiomer ( ent -SSM) separately form nano-subdomains within the liquid-ordered phase involving homophilic SSM-SSM and ent -SSM- ent -SSM interactions. In this study, the details of the subdomain formation by SSMs at the nanometer range were examined using Förster resonance energy transfer (FRET) measurements in lipid bilayers containing SSM and ent -SSM, dioleoyl-phosphatidylcholine and Cho. Although microscopy detected a stereochemical effect on partition coefficient favoring stereochemically homophilic interactions in the liquid-ordered state, it showed no significant difference in large-scale liquid-ordered domain formation by the two stereoisomers. In contrast to the uniform domains seen microscopy, FRET analysis using fluorescent donor- and acceptor-labeled SSM showed distinct differences in SM and ent- SM colocalization within nanoscale distances. Donor- and acceptor-labeled SSM showed significantly higher FRET efficiency than did donor-labeled SSM and acceptor-labeled ent -SSM in lipid vesicles composed of “racemic” (1:1) mixtures of SSM/ ent -SSM with dioleoylphosphatidylcholine and Cho. The difference in FRET efficiency indicated that SSM and ent -SSM assemble to form separate nano-subdomains. The average size of the subdomains decreased as temperature increased, and at physiological temperatures, the subdomains were found to have a single-digit nanometer radius. These results suggest that (even in the absence of ent- SM) SM-SM interactions play a crucial role in forming nano-subdomains within liquid-ordered domains and may be a key feature of lipid microdomains (or rafts) in biological membranes.

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Sphingomyelin Stereoisomers Reveal That Homophilic Interactions Cause Nanodomain Formation

Cited by 6 publications

References 0 publications

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

Enantiomers of phospholipids and cholesterol: A key to decipher lipid‐lipid interplay in membrane

Cholesterol-Induced Conformational Change in the Sphingomyelin Headgroup

Sphingomyelins and ent-Sphingomyelins Form Homophilic Nano-Subdomains within Liquid Ordered Domains

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