An atomic structure of human γ-secretase

Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined b...
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Autor*in:	Sun, Linfeng [verfasserIn] Bai, Xiao-chen Lu, Peilong Yan, Chuangye Yang, Guanghui Ma, Dan Zhou, Rui Scheres, Sjors H W Shi, Yigong

Format:	Artikel
Sprache:	Englisch

Erschienen:	2015

Schlagwörter:	Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry

Übergeordnetes Werk:	Enthalten in: Nature - London : Macmillan Publishers Limited, part of Springer Nature, 1869, 525(2015), 7568, Seite 212
Übergeordnetes Werk:	volume:525 ; year:2015 ; number:7568 ; pages:212

Links:	Link aufrufen

Katalog-ID:	OLC1969666293

Internformat


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520			\|a Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.
650		4	\|a Presenilin-1 - ultrastructure
650		4	\|a Membrane Glycoproteins - metabolism
650		4	\|a Amyloid Precursor Protein Secretases - chemistry
650		4	\|a Alzheimer Disease - genetics
650		4	\|a Membrane Glycoproteins - ultrastructure
650		4	\|a Membrane Glycoproteins - chemistry
650		4	\|a Presenilin-1 - genetics
650		4	\|a Amyloid Precursor Protein Secretases - metabolism
650		4	\|a Protein Subunits - metabolism
650		4	\|a Amyloid Precursor Protein Secretases - genetics
650		4	\|a Amyloid Precursor Protein Secretases - ultrastructure
650		4	\|a Protein Subunits - genetics
650		4	\|a Protein Subunits - chemistry
650		4	\|a Presenilin-1 - chemistry
700	1		\|a Bai, Xiao-chen \|4 oth
700	1		\|a Lu, Peilong \|4 oth
700	1		\|a Yan, Chuangye \|4 oth
700	1		\|a Yang, Guanghui \|4 oth
700	1		\|a Ma, Dan \|4 oth
700	1		\|a Zhou, Rui \|4 oth
700	1		\|a Scheres, Sjors H W \|4 oth
700	1		\|a Shi, Yigong \|4 oth
773	0	8	\|i Enthalten in \|t Nature \|d London : Macmillan Publishers Limited, part of Springer Nature, 1869 \|g 525(2015), 7568, Seite 212 \|w (DE-627)129292834 \|w (DE-600)120714-3 \|w (DE-576)014473941 \|x 0028-0836 \|7 nnns
773	1	8	\|g volume:525 \|g year:2015 \|g number:7568 \|g pages:212
856	4	2	\|u http://www.ncbi.nlm.nih.gov/pubmed/26280335
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912			\|a GBV_ILN_110
912			\|a GBV_ILN_120
912			\|a GBV_ILN_154
912			\|a GBV_ILN_160
912			\|a GBV_ILN_168
912			\|a GBV_ILN_170
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912			\|a GBV_ILN_267
912			\|a GBV_ILN_290
912			\|a GBV_ILN_294
912			\|a GBV_ILN_601
912			\|a GBV_ILN_647
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912			\|a GBV_ILN_2001
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912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4314
912			\|a GBV_ILN_4317
912			\|a GBV_ILN_4320
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4700
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952			\|d 525 \|j 2015 \|e 7568 \|h 212

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matchkey_str	article:00280836:2015----::ntmctutrohmn
hierarchy_sort_str	2015
publishDate	2015
allfields	PQ20160211 (DE-627)OLC1969666293 (DE-599)GBVOLC1969666293 (PRQ)p830-c2efcc50763d22aac2dd273b7b852805192bc90082898754fafb4f9f54bd401a0 (KEY)0072945020150000525756800212atomicstructureofhumansecretase DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sun, Linfeng verfasserin aut An atomic structure of human γ-secretase 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry Bai, Xiao-chen oth Lu, Peilong oth Yan, Chuangye oth Yang, Guanghui oth Ma, Dan oth Zhou, Rui oth Scheres, Sjors H W oth Shi, Yigong oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 525(2015), 7568, Seite 212 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:525 year:2015 number:7568 pages:212 http://www.ncbi.nlm.nih.gov/pubmed/26280335 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 525 2015 7568 212
spelling	PQ20160211 (DE-627)OLC1969666293 (DE-599)GBVOLC1969666293 (PRQ)p830-c2efcc50763d22aac2dd273b7b852805192bc90082898754fafb4f9f54bd401a0 (KEY)0072945020150000525756800212atomicstructureofhumansecretase DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sun, Linfeng verfasserin aut An atomic structure of human γ-secretase 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry Bai, Xiao-chen oth Lu, Peilong oth Yan, Chuangye oth Yang, Guanghui oth Ma, Dan oth Zhou, Rui oth Scheres, Sjors H W oth Shi, Yigong oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 525(2015), 7568, Seite 212 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:525 year:2015 number:7568 pages:212 http://www.ncbi.nlm.nih.gov/pubmed/26280335 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 525 2015 7568 212
allfields_unstemmed	PQ20160211 (DE-627)OLC1969666293 (DE-599)GBVOLC1969666293 (PRQ)p830-c2efcc50763d22aac2dd273b7b852805192bc90082898754fafb4f9f54bd401a0 (KEY)0072945020150000525756800212atomicstructureofhumansecretase DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sun, Linfeng verfasserin aut An atomic structure of human γ-secretase 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry Bai, Xiao-chen oth Lu, Peilong oth Yan, Chuangye oth Yang, Guanghui oth Ma, Dan oth Zhou, Rui oth Scheres, Sjors H W oth Shi, Yigong oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 525(2015), 7568, Seite 212 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:525 year:2015 number:7568 pages:212 http://www.ncbi.nlm.nih.gov/pubmed/26280335 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 525 2015 7568 212
allfieldsGer	PQ20160211 (DE-627)OLC1969666293 (DE-599)GBVOLC1969666293 (PRQ)p830-c2efcc50763d22aac2dd273b7b852805192bc90082898754fafb4f9f54bd401a0 (KEY)0072945020150000525756800212atomicstructureofhumansecretase DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sun, Linfeng verfasserin aut An atomic structure of human γ-secretase 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry Bai, Xiao-chen oth Lu, Peilong oth Yan, Chuangye oth Yang, Guanghui oth Ma, Dan oth Zhou, Rui oth Scheres, Sjors H W oth Shi, Yigong oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 525(2015), 7568, Seite 212 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:525 year:2015 number:7568 pages:212 http://www.ncbi.nlm.nih.gov/pubmed/26280335 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 525 2015 7568 212
allfieldsSound	PQ20160211 (DE-627)OLC1969666293 (DE-599)GBVOLC1969666293 (PRQ)p830-c2efcc50763d22aac2dd273b7b852805192bc90082898754fafb4f9f54bd401a0 (KEY)0072945020150000525756800212atomicstructureofhumansecretase DE-627 ger DE-627 rakwb eng 070 500 DNB 500 AVZ BIODIV fid Sun, Linfeng verfasserin aut An atomic structure of human γ-secretase 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function. Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry Bai, Xiao-chen oth Lu, Peilong oth Yan, Chuangye oth Yang, Guanghui oth Ma, Dan oth Zhou, Rui oth Scheres, Sjors H W oth Shi, Yigong oth Enthalten in Nature London : Macmillan Publishers Limited, part of Springer Nature, 1869 525(2015), 7568, Seite 212 (DE-627)129292834 (DE-600)120714-3 (DE-576)014473941 0028-0836 nnns volume:525 year:2015 number:7568 pages:212 http://www.ncbi.nlm.nih.gov/pubmed/26280335 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-SPO SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-FOR GBV_ILN_11 GBV_ILN_21 GBV_ILN_22 GBV_ILN_30 GBV_ILN_40 GBV_ILN_47 GBV_ILN_55 GBV_ILN_59 GBV_ILN_60 GBV_ILN_62 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_100 GBV_ILN_101 GBV_ILN_110 GBV_ILN_120 GBV_ILN_154 GBV_ILN_160 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_267 GBV_ILN_290 GBV_ILN_294 GBV_ILN_601 GBV_ILN_647 GBV_ILN_754 GBV_ILN_2001 GBV_ILN_2002 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2015 GBV_ILN_2016 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2026 GBV_ILN_2095 GBV_ILN_2116 GBV_ILN_2120 GBV_ILN_2121 GBV_ILN_2173 GBV_ILN_2219 GBV_ILN_2221 GBV_ILN_2279 GBV_ILN_2286 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4046 GBV_ILN_4125 GBV_ILN_4219 GBV_ILN_4251 GBV_ILN_4277 GBV_ILN_4302 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4317 GBV_ILN_4320 GBV_ILN_4324 GBV_ILN_4700 AR 525 2015 7568 212
language	English
source	Enthalten in Nature 525(2015), 7568, Seite 212 volume:525 year:2015 number:7568 pages:212
sourceStr	Enthalten in Nature 525(2015), 7568, Seite 212 volume:525 year:2015 number:7568 pages:212
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry
dewey-raw	070
isfreeaccess_bool	false
container_title	Nature
authorswithroles_txt_mv	Sun, Linfeng @@aut@@ Bai, Xiao-chen @@oth@@ Lu, Peilong @@oth@@ Yan, Chuangye @@oth@@ Yang, Guanghui @@oth@@ Ma, Dan @@oth@@ Zhou, Rui @@oth@@ Scheres, Sjors H W @@oth@@ Shi, Yigong @@oth@@
publishDateDaySort_date	2015-01-01T00:00:00Z
hierarchy_top_id	129292834
dewey-sort	270
id	OLC1969666293
language_de	englisch
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author	Sun, Linfeng
spellingShingle	Sun, Linfeng ddc 070 ddc 500 fid BIODIV misc Presenilin-1 - ultrastructure misc Membrane Glycoproteins - metabolism misc Amyloid Precursor Protein Secretases - chemistry misc Alzheimer Disease - genetics misc Membrane Glycoproteins - ultrastructure misc Membrane Glycoproteins - chemistry misc Presenilin-1 - genetics misc Amyloid Precursor Protein Secretases - metabolism misc Protein Subunits - metabolism misc Amyloid Precursor Protein Secretases - genetics misc Amyloid Precursor Protein Secretases - ultrastructure misc Protein Subunits - genetics misc Protein Subunits - chemistry misc Presenilin-1 - chemistry An atomic structure of human γ-secretase
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topic_title	070 500 DNB 500 AVZ BIODIV fid An atomic structure of human γ-secretase Presenilin-1 - ultrastructure Membrane Glycoproteins - metabolism Amyloid Precursor Protein Secretases - chemistry Alzheimer Disease - genetics Membrane Glycoproteins - ultrastructure Membrane Glycoproteins - chemistry Presenilin-1 - genetics Amyloid Precursor Protein Secretases - metabolism Protein Subunits - metabolism Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - ultrastructure Protein Subunits - genetics Protein Subunits - chemistry Presenilin-1 - chemistry
topic	ddc 070 ddc 500 fid BIODIV misc Presenilin-1 - ultrastructure misc Membrane Glycoproteins - metabolism misc Amyloid Precursor Protein Secretases - chemistry misc Alzheimer Disease - genetics misc Membrane Glycoproteins - ultrastructure misc Membrane Glycoproteins - chemistry misc Presenilin-1 - genetics misc Amyloid Precursor Protein Secretases - metabolism misc Protein Subunits - metabolism misc Amyloid Precursor Protein Secretases - genetics misc Amyloid Precursor Protein Secretases - ultrastructure misc Protein Subunits - genetics misc Protein Subunits - chemistry misc Presenilin-1 - chemistry
topic_unstemmed	ddc 070 ddc 500 fid BIODIV misc Presenilin-1 - ultrastructure misc Membrane Glycoproteins - metabolism misc Amyloid Precursor Protein Secretases - chemistry misc Alzheimer Disease - genetics misc Membrane Glycoproteins - ultrastructure misc Membrane Glycoproteins - chemistry misc Presenilin-1 - genetics misc Amyloid Precursor Protein Secretases - metabolism misc Protein Subunits - metabolism misc Amyloid Precursor Protein Secretases - genetics misc Amyloid Precursor Protein Secretases - ultrastructure misc Protein Subunits - genetics misc Protein Subunits - chemistry misc Presenilin-1 - chemistry
topic_browse	ddc 070 ddc 500 fid BIODIV misc Presenilin-1 - ultrastructure misc Membrane Glycoproteins - metabolism misc Amyloid Precursor Protein Secretases - chemistry misc Alzheimer Disease - genetics misc Membrane Glycoproteins - ultrastructure misc Membrane Glycoproteins - chemistry misc Presenilin-1 - genetics misc Amyloid Precursor Protein Secretases - metabolism misc Protein Subunits - metabolism misc Amyloid Precursor Protein Secretases - genetics misc Amyloid Precursor Protein Secretases - ultrastructure misc Protein Subunits - genetics misc Protein Subunits - chemistry misc Presenilin-1 - chemistry
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title	An atomic structure of human γ-secretase
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title_full	An atomic structure of human γ-secretase
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title_sort	atomic structure of human γ-secretase
title_auth	An atomic structure of human γ-secretase
abstract	Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.
abstractGer	Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.
abstract_unstemmed	Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1). Here we report an atomic structure of human γ-secretase at 3.4 Å resolution, determined by single-particle cryo-electron microscopy. Mutations derived from Alzheimer's disease affect residues at two hotspots in PS1, each located at the centre of a distinct four transmembrane segment (TM) bundle. TM2 and, to a lesser extent, TM6 exhibit considerable flexibility, yielding a plastic active site and adaptable surrounding elements. The active site of PS1 is accessible from the convex side of the TM horseshoe, suggesting considerable conformational changes in nicastrin extracellular domain after substrate recruitment. Component protein APH-1 serves as a scaffold, anchoring the lone transmembrane helix from nicastrin and supporting the flexible conformation of PS1. Ordered phospholipids stabilize the complex inside the membrane. Our structure serves as a molecular basis for mechanistic understanding of γ-secretase function.
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container_issue	7568
title_short	An atomic structure of human γ-secretase
url	http://www.ncbi.nlm.nih.gov/pubmed/26280335
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author2	Bai, Xiao-chen Lu, Peilong Yan, Chuangye Yang, Guanghui Ma, Dan Zhou, Rui Scheres, Sjors H W Shi, Yigong
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An atomic structure of human γ-secretase

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