登録情報 データベース : EMDB / ID : EMD-17112 ダウンロードとリンクタイトル Structure of apo form of human gamma-secretase PSEN1 APH-1B isoform reconstituted into lipid nanodisc マップデータLocal resolution filtered masked map after pixel size calibration 詳細 試料複合体 : Gamma secretaseタンパク質・ペプチド : Nicastrinタンパク質・ペプチド : Presenilin-1 CTF12タンパク質・ペプチド : Gamma-secretase subunit APH-1Bタンパク質・ペプチド : Gamma-secretase subunit PEN-2リガンド : 2-acetamido-2-deoxy-beta-D-glucopyranoseリガンド : 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE 詳細 キーワード intramembrane proteolysis / protease / di-aspartyl protease / Alzheimer's disease / complex / MEMBRANE PROTEIN機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / smooth endoplasmic reticulum calcium ion homeostasis ... Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / negative regulation of core promoter binding / positive regulation of endopeptidase activity / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / short-term synaptic potentiation / positive regulation of amyloid precursor protein biosynthetic process / smooth endoplasmic reticulum calcium ion homeostasis / Noncanonical activation of NOTCH3 / protein catabolic process at postsynapse / TGFBR3 PTM regulation / sequestering of calcium ion / Notch receptor processing / synaptic vesicle targeting / negative regulation of axonogenesis / positive regulation of coagulation / central nervous system myelination / membrane protein intracellular domain proteolysis / choline transport / T cell activation involved in immune response / skin morphogenesis / NOTCH4 Activation and Transmission of Signal to the Nucleus / dorsal/ventral neural tube patterning / ciliary rootlet / neural retina development / regulation of resting membrane potential / L-glutamate import across plasma membrane / regulation of phosphorylation / Regulated proteolysis of p75NTR / myeloid dendritic cell differentiation / brain morphogenesis / locomotion / endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of synaptic vesicle cycle / regulation of long-term synaptic potentiation / regulation of postsynapse organization / embryonic limb morphogenesis / cell fate specification / astrocyte activation involved in immune response / regulation of canonical Wnt signaling pathway / myeloid cell homeostasis / aggresome / skeletal system morphogenesis / azurophil granule membrane / growth factor receptor binding / 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 / glutamate receptor signaling pathway / Golgi cisterna membrane / G protein-coupled dopamine receptor signaling pathway / positive regulation of amyloid fibril formation / protein glycosylation / blood vessel development / mitochondrial transport / amyloid-beta formation / heart looping / amyloid precursor protein catabolic process / positive regulation of dendritic spine development / regulation of neuron projection development / positive regulation of receptor recycling / cerebral cortex cell migration / nuclear outer membrane / adult behavior / smooth endoplasmic reticulum / membrane protein ectodomain proteolysis / negative regulation of apoptotic signaling pathway / EPH-ephrin mediated repulsion of cells / autophagosome assembly / negative regulation of ubiquitin-dependent protein catabolic process / endopeptidase activator activity / neuron development / NOTCH2 Activation and Transmission of Signal to the Nucleus / T cell proliferation / somitogenesis / hematopoietic progenitor cell differentiation / regulation of synaptic transmission, glutamatergic / Nuclear signaling by ERBB4 / calcium ion homeostasis / NRIF signals cell death from the nucleus / transport vesicle / Activated NOTCH1 Transmits Signal to the Nucleus / rough endoplasmic reticulum / Degradation of the extracellular matrix / Notch signaling pathway / neuron projection maintenance / astrocyte activation / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / thymus development / cerebellum development / positive regulation of glycolytic process / epithelial cell proliferation / dendritic shaft / post-embryonic development / PDZ domain binding / neuromuscular junction / apoptotic signaling pathway / Constitutive Signaling by NOTCH1 PEST Domain Mutants 類似検索 - 分子機能 Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe ... Peptidase A22A, presenilin 1 / Gamma-secretase subunit Aph-1 / Gamma-secretase aspartyl protease complex, presenilin enhancer-2 subunit / Aph-1 protein / Presenilin enhancer-2 subunit of gamma secretase / Peptidase A22A, presenilin / Presenilin, C-terminal / Presenilin / Nicastrin / Nicastrin, small lobe / Nicastrin large lobe / Nicastrin small lobe / Presenilin/signal peptide peptidase / Presenilin, signal peptide peptidase, family 類似検索 - ドメイン・相同性 Presenilin-1 / Gamma-secretase subunit APH-1B / Nicastrin / Gamma-secretase subunit PEN-2 類似検索 - 構成要素生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.3 Å 詳細 データ登録者Odorcic I / Chavez Gutierrez L / Efremov RG 資金援助 ベルギー, 4件 詳細 詳細を隠すOrganization Grant number 国 Research Foundation - Flanders (FWO) G0B2519N ベルギー Research Foundation - Flanders (FWO) G008023N ベルギー Research Foundation - Flanders (FWO) G0H5916N ベルギー Research Foundation - Flanders (FWO) G054617N ベルギー
引用ジャーナル : Nat Commun / 年 : 2024タイトル : Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform.著者 : Ivica Odorčić / Mohamed Belal Hamed / Sam Lismont / Lucía Chávez-Gutiérrez / Rouslan G Efremov / 要旨 : Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase ... Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer's disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aβ peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer's pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aβ, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aβ46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aβ46 structure reveals an interaction between Aβ46 and loop 1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis. 履歴 登録 2023年4月12日 - ヘッダ(付随情報) 公開 2024年4月24日 - マップ公開 2024年4月24日 - 更新 2024年10月23日 - 現状 2024年10月23日 処理サイト : PDBe / 状態 : 公開
すべて表示 表示を減らす