Journal
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
Volume 1861, Issue 4, Pages 887-896Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamem.2019.01.005
Keywords
Polyunsaturated fatty acids (PUFA); Docosahexaenoic acid (DHA); Cholesterol; Nicotinic acetylcholine receptor; nAChR partitioning; Liquid order (l(o)); Liquid disorder (l(do)); Lipid-protein interactions; Lipid rafts
Categories
Funding
- NSF [MCB1330728]
- NIH [P01GM55876-14A1]
- Research Corporation for Scientific Advancement
- National Science Foundation XSEDE program [NSF-MCB110149]
- Rutgers University Office of Advanced Research Computing (OARC)
- Rutgers Discovery Informatics Institute (RDI2)
- Rutgers
- State of New Jersey
- [NSF-DBI1126052]
Ask authors/readers for more resources
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 l(o)) domains or cholesterol-poor liquid-disordered (l(do)) 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 Dipalmitoylphosphatidylcholine:Cholesterol (DPPC:CHOL) 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 beta 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) 5-10 angstrom. 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 l(do) domain that was present, regardless of whether the l(do) or l(o) 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available