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Many of the mutations encountered in early onset familial Alzheimer\u2019s disease are linked to presenilin\u00a01, the catalytic component of \u03b3-secretase, whose active form requires its endoproteolytic cleavage into N-terminal and C-terminal fragments. Although there is general agreement regarding the topology of the N-terminal fragment, studies of the C-terminal fragment have yielded ambiguous and contradictory results that may be difficult to reconcile in the absence of structural information. Here we present the first structure of the C-terminal fragment of human presenilin\u00a01, as obtained from NMR studies in SDS micelles. The structure reveals a topology where the membrane is likely traversed three times in accordance with the more generally accepted nine transmembrane domain model of presenilin\u00a01, but contains unique structural features adapted to accommodate the unusual intramembrane catalysis. These include a putative half-membrane-spanning helix N-terminally harboring the catalytic aspartate, a severely kinked helical structure toward the C\u00a0terminus as well as a soluble helix in the assumed-to-be unstructured N-terminal loop.<\/jats:p>","DOI":"10.1073\/pnas.1000778107","type":"journal-article","created":{"date-parts":[[2010,5,5]],"date-time":"2010-05-05T22:53:50Z","timestamp":1273100030000},"page":"9644-9649","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":74,"title":["Structural investigation of the C-terminal catalytic fragment of presenilin 1"],"prefix":"10.1073","volume":"107","author":[{"given":"Solmaz","family":"Sobhanifar","sequence":"first","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt\/Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Schneider","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt\/Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"L\u00f6hr","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt\/Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Gottstein","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt\/Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Ikeya","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance and Cluster of Excellence Macromolecular Complexes, Goethe University, 60438 Frankfurt\/Main, Germany;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krzysztof","family":"Mlynarczyk","sequence":"additional","affiliation":[{"name":"Laboratory of Biomodeling, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland;"},{"name":"Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojciech","family":"Pulawski","sequence":"additional","affiliation":[{"name":"Laboratory of Biomodeling, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umesh","family":"Ghoshdastider","sequence":"additional","affiliation":[{"name":"Laboratory of Biomodeling, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michal","family":"Kolinski","sequence":"additional","affiliation":[{"name":"Laboratory of Biomodeling, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Slawomir","family":"Filipek","sequence":"additional","affiliation":[{"name":"Laboratory of Biomodeling, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland;"},{"name":"Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland; 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J Biol Chem 277, 32046\u201332053 (2002).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_2_2","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1016\/j.nbd.2009.05.024","article-title":"Soluble fibrillar oligomer levels are elevated in Alzheimer\u2019s disease brain and correlate with cognitive dysfunction","volume":"35","author":"Tomic JL","year":"2009","unstructured":"JL Tomic, A Pensalfini, E Head, CG Glabe, Soluble fibrillar oligomer levels are elevated in Alzheimer\u2019s disease brain and correlate with cognitive dysfunction. Neurobiol Dis 35, 352\u2013358 (2009).","journal-title":"Neurobiol Dis"},{"key":"e_1_3_4_3_2","doi-asserted-by":"crossref","first-page":"33985","DOI":"10.1074\/jbc.M705248200","article-title":"Active gamma-secretase complexes contain only one of each component","volume":"282","author":"Sato T","year":"2007","unstructured":"T Sato, et al., Active gamma-secretase complexes contain only one of each component. J Biol Chem 282, 33985\u201333993 (2007).","journal-title":"J Biol Chem"},{"key":"e_1_3_4_4_2","doi-asserted-by":"crossref","first-page":"10836","DOI":"10.1073\/pnas.90.22.10836","article-title":"beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease","volume":"90","author":"Roher AE","year":"1993","unstructured":"AE Roher, et al., beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease. 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Biochemistry 43, 6208\u20136218 (2004).","journal-title":"Biochemistry"},{"key":"e_1_3_4_8_2","doi-asserted-by":"crossref","first-page":"6889","DOI":"10.1073\/pnas.0602321103","article-title":"Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores","volume":"103","author":"Lazarov VK","year":"2006","unstructured":"VK Lazarov, et al., Electron microscopic structure of purified, active gamma-secretase reveals an aqueous intramembrane chamber and two pores. Proc Natl Acad Sci USA 103, 6889\u20136894 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.jmb.2008.10.078","article-title":"Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution","volume":"385","author":"Osenkowski P","year":"2009","unstructured":"P Osenkowski, et al., Cryoelectron microscopy structure of purified gamma-secretase at 12 A resolution. J Mol Biol 385, 642\u2013652 (2009).","journal-title":"J Mol Biol"},{"key":"e_1_3_4_10_2","doi-asserted-by":"crossref","first-page":"4738","DOI":"10.1038\/sj.emboj.7600478","article-title":"The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity","volume":"23","author":"Kaether C","year":"2004","unstructured":"C Kaether, et al., The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity. 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Neurobiol Dis 15, 654\u2013666 (2004).","journal-title":"Neurobiol Dis"},{"key":"e_1_3_4_12_2","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1111\/j.1471-4159.2005.03548.x","article-title":"C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation","volume":"96","author":"Wang J","year":"2006","unstructured":"J Wang, et al., C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation. 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