{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T17:32:36Z","timestamp":1793727156356,"version":"4.6.1"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"50","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,12,16]]},"abstract":"<jats:p>\u03b1-Synuclein is known to play a causative role in Parkinson disease. Although its physiological functions are not fully understood, \u03b1-synuclein has been shown to interact with synaptic vesicles and modulate neurotransmitter release. However, the structure of its physiologically relevant membrane-bound state remains unknown. Here we developed a site-directed spin labeling and EPR-based approach for determining the structure of \u03b1-synuclein bound to a lipid bilayer. Continuous-wave EPR was used to assign local secondary structure and to determine the membrane immersion depth of lipid-exposed residues, whereas pulsed EPR was used to map long-range distances. The structure of \u03b1-synuclein was built and refined by using simulated annealing molecular dynamics restrained by the immersion depths and distances. We found that \u03b1-synuclein forms an extended, curved \u03b1-helical structure that is over 90 aa in length. The monomeric helix has a superhelical twist similar to that of right-handed coiled-coils which, like \u03b1-synuclein, contain 11-aa repeats, but which are soluble, oligomeric proteins (rmsd = 0.82 \u212b). The \u03b1-synuclein helix extends parallel to the curved membrane in a manner that allows conserved Lys and Glu residues to interact with the zwitterionic headgroups, while uncharged residues penetrate into the acyl chain region. This structural arrangement is significantly different from that of \u03b1-synuclein in the presence of the commonly used membrane-mimetic detergent SDS, which induces the formation of two antiparallel helices. Our structural analysis emphasizes the importance of studying membrane protein structure in a bilayer environment.<\/jats:p>","DOI":"10.1073\/pnas.0807826105","type":"journal-article","created":{"date-parts":[[2008,12,9]],"date-time":"2008-12-09T20:44:57Z","timestamp":1228855497000},"page":"19666-19671","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":499,"title":["Structure of membrane-bound \u03b1-synuclein from site-directed spin labeling and computational refinement"],"prefix":"10.1073","volume":"105","author":[{"given":"Christine C.","family":"Jao","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,"},{"name":"Zilkha Neurogenetic Institute and Arnold and Mabel Beckman Macular Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balachandra G.","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,"},{"name":"Zilkha Neurogenetic Institute and Arnold and Mabel Beckman Macular Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeannie","family":"Chen","sequence":"additional","affiliation":[{"name":"Zilkha Neurogenetic Institute and Arnold and Mabel Beckman Macular Research Center, and"},{"name":"Departments of cOphthalmology and"},{"name":"Cell and Neurobiology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian S.","family":"Haworth","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,"},{"name":"Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, Los Angeles, CA 90033"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Langen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology,"},{"name":"Zilkha Neurogenetic Institute and Arnold and Mabel Beckman Macular Research Center, and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2008,12,16]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M108414200"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M107045200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn983"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M305326200"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1594-04.2004"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1385\/MN:30:1:001"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-007-7217-5"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi701522m"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e07-08-0827"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00249-007-0237-0"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0896-6273(95)90302-X"},{"key":"e_1_3_3_12_2","first-page":"201","article-title":"Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease","volume":"148","author":"Masliah E","year":"1996","unstructured":"E Masliah, A Iwai, M Mallory, K Ueda, T Saitoh, Altered presynaptic protein NACP is associated with plaque formation and neurodegeneration in Alzheimer's disease. Am J Pathol 148, 201\u2013210 (1996).","journal-title":"Am J Pathol"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80886-7"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-09-03214.2000"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-20-08797.2002"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710685105"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.16.9443"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M512292200"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.2001.4538"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400553101"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M411805200"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja8010429"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja801594s"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/78956"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(98)80158-9"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2006.08.008"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M213128200"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(03)00520-5"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja063122l"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmre.1999.1944"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0076-6879(07)23004-6"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0802515105"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1039\/b614920k"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03166213"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/0010-4655(95)00041-D"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.282.5393.1462"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/79006"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.06.051"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.5.1667"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmr.2004.10.012"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki524"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0807826105","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:12:22Z","timestamp":1649787142000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0807826105"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,12,16]]},"references-count":41,"journal-issue":{"issue":"50","published-print":{"date-parts":[[2008,12,16]]}},"alternative-id":["10.1073\/pnas.0807826105"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0807826105","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2008,12,16]]},"assertion":[{"value":"2008-08-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2008-12-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}