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基本情報
登録情報 | データベース: PDB / ID: 5fn5 | ||||||
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タイトル | Cryo-EM structure of gamma secretase in class 3 of the apo- state ensemble | ||||||
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![]() | HYDROLASE | ||||||
機能・相同性 | ![]() Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of coagulation / negative regulation of core promoter binding / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / protein catabolic process at postsynapse / positive regulation of amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / Noncanonical activation of NOTCH3 / sequestering of calcium ion / Notch receptor processing / choline transport / central nervous system myelination / synaptic vesicle targeting / membrane protein intracellular domain proteolysis / negative regulation of axonogenesis / regulation of resting membrane potential / T cell activation involved in immune response / NOTCH4 Activation and Transmission of Signal to the Nucleus / skin morphogenesis / growth factor receptor binding / regulation of synaptic vesicle cycle / dorsal/ventral neural tube patterning / neural retina development / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / Regulated proteolysis of p75NTR / cerebral cortex cell migration / regulation of phosphorylation / metanephros development / brain morphogenesis / endoplasmic reticulum calcium ion homeostasis / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / amyloid precursor protein metabolic process / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / aggresome / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / skeletal system morphogenesis / cell fate specification / ciliary rootlet / myeloid cell homeostasis / regulation of postsynapse organization / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; アスパラギン酸プロテアーゼ / positive regulation of amyloid fibril formation / Golgi cisterna membrane / adult behavior / mitochondrial transport / positive regulation of dendritic spine development / positive regulation of receptor recycling / blood vessel development / regulation of neuron projection development / heart looping / protein glycosylation / amyloid precursor protein catabolic process / amyloid-beta formation / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / endopeptidase activator activity / autophagosome assembly / EPH-ephrin mediated repulsion of cells / smooth endoplasmic reticulum / neuron development / hematopoietic progenitor cell differentiation / negative regulation of ubiquitin-dependent protein catabolic process / somitogenesis / calcium ion homeostasis / T cell proliferation / Nuclear signaling by ERBB4 / rough endoplasmic reticulum / epithelial cell proliferation / Notch signaling pathway / regulation of synaptic transmission, glutamatergic / neuron projection maintenance / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / Degradation of the extracellular matrix / positive regulation of glycolytic process / NRIF signals cell death from the nucleus / Activated NOTCH1 Transmits Signal to the Nucleus / cerebellum development / post-embryonic development / thymus development / negative regulation of protein phosphorylation / dendritic shaft / PDZ domain binding / apoptotic signaling pathway / cell-cell adhesion / synapse organization 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 4.3 Å | ||||||
![]() | Bai, X.C. / Rajendra, E. / Yang, G.H. / Shi, Y.G. / Scheres, S.H.W. | ||||||
![]() | ![]() タイトル: Sampling the conformational space of the catalytic subunit of human γ-secretase. 著者: Xiao-chen Bai / Eeson Rajendra / Guanghui Yang / Yigong Shi / Sjors H W Scheres / ![]() ![]() 要旨: Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein ...Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of γ-secretase. In addition, we present a γ-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain. | ||||||
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構造の表示
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 237.5 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 828.2 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 861.6 KB | 表示 | |
XML形式データ | ![]() | 38.3 KB | 表示 | |
CIF形式データ | ![]() | 59.1 KB | 表示 | |
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-関連構造データ
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 78483.570 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: A DRUG DAPT WAS BOUND TO GAMMA SECRETASE COMPLEX / 由来: (組換発現) ![]() ![]() |
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#2: タンパク質 | 分子量: 52713.535 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: A DRUG DAPT WAS BOUND TO GAMMA SECRETASE COMPLEX / 由来: (組換発現) ![]() ![]() 参照: UniProt: P49768, 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; アスパラギン酸プロテアーゼ |
#3: タンパク質 | 分子量: 29017.943 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: A DRUG DAPT WAS BOUND TO GAMMA SECRETASE COMPLEX / 由来: (組換発現) ![]() ![]() |
#4: タンパク質 | 分子量: 12038.029 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: A DRUG DAPT WAS BOUND TO GAMMA SECRETASE COMPLEX / 由来: (組換発現) ![]() ![]() |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: GAMMA SECRETASE / タイプ: COMPLEX |
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緩衝液 | 名称: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35 / pH: 7.4 / 詳細: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35 |
試料 | 濃度: 6 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | 詳細: HOLEY CARBON |
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 詳細: LIQUID ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS / 日付: 2014年10月25日 |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 81000 X / 倍率(補正後): 35714 X / 最大 デフォーカス(公称値): 3200 nm / 最小 デフォーカス(公称値): 700 nm / Cs: 2.7 mm |
試料ホルダ | 温度: 85 K |
撮影 | 電子線照射量: 38 e/Å2 フィルム・検出器のモデル: GATAN K2 QUANTUM (4k x 4k) |
画像スキャン | デジタル画像の数: 2000 |
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解析
対称性 | 点対称性: C1 (非対称) | ||||||||||||
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3次元再構成 | 解像度: 4.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 66720 / Refinement type: HALF-MAPS REFINED INDEPENDENTLY / 対称性のタイプ: POINT | ||||||||||||
精密化 | 最高解像度: 4.3 Å | ||||||||||||
精密化ステップ | サイクル: LAST / 最高解像度: 4.3 Å
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