Publication Date:
2015-08-19
Description:
Dysfunction of the intramembrane protease gamma-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 gamma-secretase at 3.4 A 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 gamma-secretase function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568306/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4568306/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bai, Xiao-chen -- Yan, Chuangye -- Yang, Guanghui -- Lu, Peilong -- Ma, Dan -- Sun, Linfeng -- Zhou, Rui -- Scheres, Sjors H W -- Shi, Yigong -- MC_UP_A025_101/Medical Research Council/United Kingdom -- MC_UP_A025_1013/Medical Research Council/United Kingdom -- England -- Nature. 2015 Sep 10;525(7568):212-7. doi: 10.1038/nature14892. Epub 2015 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26280335" target="_blank"〉PubMed〈/a〉
Keywords:
Alzheimer Disease/genetics
;
Amyloid Precursor Protein
;
Secretases/*chemistry/genetics/metabolism/*ultrastructure
;
Binding Sites
;
*Cryoelectron Microscopy
;
Humans
;
Membrane Glycoproteins/*chemistry/metabolism/*ultrastructure
;
Models, Molecular
;
Mutation
;
Presenilin-1/*chemistry/genetics/*ultrastructure
;
Protein Structure, Tertiary
;
Protein Subunits/chemistry/genetics/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
