Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation.
Biochim Biophys Acta Biomembr
; 1861(4): 887-896, 2019 04 01.
Article
in En
| MEDLINE
| ID: mdl-30664881
ABSTRACT
Reconstituted nicotinic acetylcholine receptors (nAChRs) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and cholesterol affects the organization of nAChRs within domain-forming membranes, but whether nAChR partitions to cholesterol-rich liquid-ordered ("raft" or lo) domains or cholesterol-poor liquid-disordered (ldo) domains is unknown. We use coarse-grained molecular dynamics simulations to observe spontaneous interactions of cholesterol, saturated lipids, and polyunsaturated (PUFA) lipids with nAChRs. In binary DipalmitoylphosphatidylcholineCholesterol (DPPCCHOL) mixtures, both CHOL and DPPC acyl chains were observed spontaneously entering deep "non-annular" cavities in the nAChR TMD, particularly at the subunit interface and the ß subunit center, facilitated by the low amino acid density in the cryo-EM structure of nAChR in a native membrane. Cholesterol was highly enriched in the annulus around the TMD, but this effect extended over (at most) 5-10â¯Å. In domain-forming ternary mixtures containing PUFAs, the presence of a single receptor did not significantly affect the likelihood of domain formation. nAChR partitioned to any cholesterol-poor ldo domain that was present, regardless of whether the ldo or lo domain lipids had PC or PE headgroups. Enrichment of PUFAs among boundary lipids was positively correlated with their propensity for demixing from cholesterol-rich phases. Long n-3 chains (tested here with Docosahexaenoic Acid, DHA) were highly enriched in annular and non-annular embedded sites, partially displacing cholesterol and completely displacing DPPC, and occupying sites even deeper within the bundle. Shorter n-6 chains were far less effective at displacing cholesterol from non-annular sites.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Torpedo
/
Receptors, Nicotinic
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Fish Proteins
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Molecular Dynamics Simulation
/
Lipid Bilayers
Limits:
Animals
Language:
En
Journal:
Biochim Biophys Acta Biomembr
Year:
2019
Document type:
Article
Affiliation country: