Alpha-synuclein selectively binds to anionic phospholipids embedded in liquid-disordered domains.
Previous studies indicate that binding of alpha-synuclein to membranes is critical for its physiological function and the development of Parkinson's disease (PD). Here, we have investigated the association of fluorescence-labeled alpha-synuclein variants with different types of giant unilamellar vesicles using confocal microscopy. We found that alpha-synuclein binds with high affinity to anionic phospholipids, when they are embedded in a liquid-disordered as opposed to a liquid-ordered environment. This indicates that not only electrostatic forces but also lipid packing and hydrophobic interactions are critical for the association of alpha-synuclein with membranes in vitro. When compared to wild-type alpha-synuclein, the disease-causing alpha-synuclein variant A30P bound less efficiently to anionic phospholipids, while the variant E46K showed enhanced binding. This suggests that the natural association of alpha-synuclein with membranes is altered in the inherited forms of Parkinson's disease.
Stöckl
Martin
M
Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, Institut für Biologie/Biophysik, Invalidenstr. 43, D-10115 Berlin, Germany.
Fischer
Patricia
P
Wanker
Erich
E
Herrmann
Andreas
A
D000595:Amino Acid Sequence; D000838:Anions / Q000378:metabolism*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry; D005456:Fluorescent Dyes / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D008055:Lipids / Q000737:chemistry; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics; D010712:Phosphatidic Acids / Q000737:chemistry; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D010715:Phosphatidylglycerols / Q000737:chemistry; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D010718:Phosphatidylserines / Q000737:chemistry; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012235:Rhodamines / Q000378:metabolism; D055672:Static Electricity; D013499:Surface Properties; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*
D000838:Anions; D005227:Fatty Acids; D005456:Fluorescent Dyes; D008055:Lipids; D010712:Phosphatidic Acids; D010713:Phosphatidylcholines; D010715:Phosphatidylglycerols; D019269:Phosphatidylinositol 4,5-Diphosphate; D010718:Phosphatidylserines; D010743:Phospholipids; D012235:Rhodamines; D053835:Unilamellar Liposomes; D051844:alpha-Synuclein; C037657:dioleoylphosphatidic acid; C005358:tetramethylrhodamine; C051388:1,2-dioleoyl-sn-glycero-3-phosphoglycerol; C042511:1,2-dioleoylphosphatidylserine; C044745:1-palmitoyl-2-(6-(N-(7-nitrobenz)-2-oxa-1,3-diazol-4-yl)aminocaproyl)phosphatidylcholine; C017251:1,2-oleoylphosphatidylcholine