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基本情報
登録情報 | ![]() | |||||||||
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タイトル | Cryo-EM structure of human gamma-secretase in complex with Abeta49 | |||||||||
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![]() | Intramembrane protease / gamma-secretase / presenilin-1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-HYDROLASE complex | |||||||||
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 / regulation of phosphorylation / regulation of epidermal growth factor-activated receptor activity / metanephros development / cytosolic mRNA polyadenylation / collateral sprouting in absence of injury / microglia development / brain morphogenesis / regulation of synapse structure or activity / regulation of Wnt signaling pathway / endoplasmic reticulum calcium ion homeostasis / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / synaptic assembly at neuromuscular junction / signaling receptor activator activity / nuclear outer membrane / glutamate receptor signaling pathway / locomotion / axon midline choice point recognition / smooth endoplasmic reticulum calcium ion homeostasis / amyloid precursor protein metabolic process / regulation of canonical Wnt signaling pathway / astrocyte activation involved in immune response / aggresome / regulation of spontaneous synaptic transmission / regulation of long-term synaptic potentiation / mating behavior / embryonic limb morphogenesis / skeletal system morphogenesis / NMDA selective glutamate receptor signaling pathway / cell fate specification / ciliary rootlet / myeloid cell homeostasis / regulation of postsynapse organization / Lysosome Vesicle Biogenesis / PTB domain binding / azurophil granule membrane / G protein-coupled dopamine receptor signaling pathway / Golgi-associated vesicle / 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 / neuron remodeling / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / adult behavior / Golgi cisterna membrane / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / positive regulation of dendritic spine development / mitochondrial transport / positive regulation of receptor recycling / nuclear envelope lumen / COPII-coated ER to Golgi transport vesicle / suckling behavior / blood vessel development / regulation of neuron projection development / dendrite development / heart looping / protein glycosylation / presynaptic active zone / cerebral cortex cell migration / amyloid precursor protein catabolic process / modulation of excitatory postsynaptic potential / amyloid-beta formation / TRAF6 mediated NF-kB activation / Advanced glycosylation endproduct receptor signaling / neuromuscular process controlling balance / The NLRP3 inflammasome / negative regulation of apoptotic signaling pathway / membrane protein ectodomain proteolysis / regulation of presynapse assembly / transition metal ion binding / intracellular copper ion homeostasis 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.9 Å | |||||||||
![]() | Guo X / Yan C / Lei J / Zhou R / Shi Y / Jia B / Jing D | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Molecular mechanism of substrate recognition and cleavage by human γ-secretase. 著者: Xuefei Guo / Haotian Li / Chuangye Yan / Jianlin Lei / Rui Zhou / Yigong Shi / ![]() 要旨: Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step ...Successive cleavages of amyloid precursor protein C-terminal fragment with 99 residues (APP-C99) by γ-secretase result in amyloid-β (Aβ) peptides of varying lengths. Most cleavages have a step size of three residues. To elucidate the underlying mechanism, we determined the atomic structures of human γ-secretase bound individually to APP-C99, Aβ49, Aβ46, and Aβ43. In all cases, the substrate displays the same structural features: a transmembrane α-helix, a three-residue linker, and a β-strand that forms a hybrid β-sheet with presenilin 1 (PS1). Proteolytic cleavage occurs just ahead of the substrate β-strand. Each cleavage is followed by unwinding and translocation of the substrate α-helix by one turn and the formation of a new β-strand. This mechanism is consistent with existing biochemical data and may explain the cleavages of other substrates by γ-secretase. | |||||||||
履歴 |
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構造の表示
添付画像 |
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ダウンロードとリンク
-EMDBアーカイブ
マップデータ | ![]() | 117.9 MB | ![]() | |
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ヘッダ (付随情報) | ![]() ![]() | 20.2 KB 20.2 KB | 表示 表示 | ![]() |
画像 | ![]() | 132.6 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
その他 | ![]() ![]() | 115.7 MB 115.7 MB | ||
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 8x52MC ![]() 8x53C ![]() 8x54C M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
EMDBのページ | ![]() ![]() |
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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.0979 Å | ||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-ハーフマップ: #2
ファイル | emd_38059_half_map_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: #1
ファイル | emd_38059_half_map_2.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
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試料の構成要素
-全体 : Human gamma-secretase in complex with Abeta49
全体 | 名称: Human gamma-secretase in complex with Abeta49 |
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要素 |
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-超分子 #1: Human gamma-secretase in complex with Abeta49
超分子 | 名称: Human gamma-secretase in complex with Abeta49 / タイプ: complex / ID: 1 / 親要素: 0 / 含まれる分子: #1-#5 |
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由来(天然) | 生物種: ![]() |
-分子 #1: Amyloid-beta precursor protein
分子 | 名称: Amyloid-beta precursor protein / タイプ: protein_or_peptide / ID: 1 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 13.800604 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MDAEFRHDSG YEVHHQKLVF FAEDVGSNCG AIIGLMVGGV VIATVIVITL VMLKKKQYTS IHHGVVEVDA AVTPEERHLS KMQQNGYEN PTYKFFEQMQ NEQKLISEED LLEHHHHHHH H UniProtKB: Amyloid-beta precursor protein |
-分子 #2: Nicastrin
分子 | 名称: Nicastrin / タイプ: protein_or_peptide / ID: 2 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 78.473555 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG ...文字列: MATAGGGSGA DPGSRGLLRL LSFCVLLAGL CRGNSVERKI YIPLNKTAPC VRLLNATHQI GCQSSISGDT GVIHVVEKEE DLQWVLTDG PNPPYMVLLE SKHFTRDLME KLKGRTSRIA GLAVSLTKPS PASGFSPSVQ CPNDGFGVYS NSYGPEFAHC R EIQWNSLG NGLAYEDFSF PIFLLEDENE TKVIKQCYQD HNLSQNGSAP TFPLCAMQLF SHMHAVISTA TCMRRSSIQS TF SCNPEIV CDPLSDYNVW SMLKPINTTG TLKPDDRVVV AATRLDSRSF FWNVAPGAES AVASFVTQLA AAEALQKAPD VTT LPRNVM FVFFQGETFD YIGSSRMVYD MEKGKFPVQL ENVDSFVELG QVALRTSLEL WMHTDPVSQK NESVRNQVED LLAT LEKSG AGVPAVILRR PNQSQPLPPS SLQRFLRARN ISGVVLADHS GAFHNKYYQS IYDTAENINV SYPEWLSPEE DLNFV TDTA KALADVATVL GRALYELAGG TNFSDTVQAD PQTVTRLLYG FLIKANNSWF QSILRQDLRS YLGDGPLQHY IAVSSP TNT TYVVQYALAN LTGTVVNLTR EQCQDPSKVP SENKDLYEYS WVQGPLHSNE TDRLPRCVRS TARLARALSP AFELSQW SS TEYSTWTESR WKDIRARIFL IASKELELIT LTVGFGILIF SLIVTYCINA KADVLFIAPR EPGAVSY UniProtKB: Nicastrin |
-分子 #3: Presenilin-1
分子 | 名称: Presenilin-1 / タイプ: protein_or_peptide / ID: 3 / コピー数: 1 / 光学異性体: LEVO EC番号: 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 |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 52.712551 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII ...文字列: MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR QVVEQDEEED EELTLKYGAK HVIMLFVPV TLCMVVVVAT IKSVSFYTRK DGQLIYTPFT EDTETVGQRA LHSILNAAIM ISVIVVMTIL LVVLYKYRCY K VIHAWLII SSLLLLFFFS FIYLGEVFKT YNVAVDYITV ALLIWNFGVV GMISIHWKGP LRLQQAYLIM ISALMALVFI KY LPEWTAW LILAVISVYD LVAVLCPKGP LRMLVETAQE RNETLFPALI YSSTMVWLVN MAEGDPEAQR RVSKNSKYNA EST ERESQD TVAENDDGGF SEEWEAQRDS HLGPHRSTPE SRAAVQELSS SILAGEDPEE RGVKLGLGNF IFYSVLVGKA SATA SGDWN TTIACFVAIL IGLCLTLLLL AIFKKALPAL PISITFGLVF YFATDYLVQP FMDQLAFHQF YI UniProtKB: Presenilin-1 |
-分子 #4: Gamma-secretase subunit APH-1A
分子 | 名称: Gamma-secretase subunit APH-1A / タイプ: protein_or_peptide / ID: 4 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 29.017943 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII ...文字列: MGAAVFFGCT FVAFGPAFAL FLITVAGDPL RVIILVAGAF FWLVSLLLAS VVWFILVHVT DRSDARLQYG LLIFGAAVSV LLQEVFRFA YYKLLKKADE GLASLSEDGR SPISIRQMAY VSGLSFGIIS GVFSVINILA DALGPGVVGI HGDSPYYFLT S AFLTAAII LLHTFWGVVF FDACERRRYW ALGLVVGSHL LTSGLTFLNP WYEASLLPIY AVTVSMGLWA FITAGGSLRS IQ RSLLCRR QEDSRVMVYS ALRIPPED UniProtKB: Gamma-secretase subunit APH-1A |
-分子 #5: Gamma-secretase subunit PEN-2
分子 | 名称: Gamma-secretase subunit PEN-2 / タイプ: protein_or_peptide / ID: 5 / コピー数: 1 / 光学異性体: LEVO |
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由来(天然) | 生物種: ![]() |
分子量 | 理論値: 12.038029 KDa |
組換発現 | 生物種: ![]() |
配列 | 文字列: MNLERVSNEE KLNLCRKYYL GGFAFLPFLW LVNIFWFFRE AFLVPAYTEQ SQIKGYVWRS AVGFLFWVIV LTSWITIFQI YRPRWGALG DYLSFTIPLG TP UniProtKB: Gamma-secretase subunit PEN-2 |
-分子 #8: 2-acetamido-2-deoxy-beta-D-glucopyranose
分子 | 名称: 2-acetamido-2-deoxy-beta-D-glucopyranose / タイプ: ligand / ID: 8 / コピー数: 6 / 式: NAG |
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分子量 | 理論値: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-分子 #9: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE
分子 | 名称: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / タイプ: ligand / ID: 9 / コピー数: 2 / 式: PC1 |
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分子量 | 理論値: 790.145 Da |
Chemical component information | ![]() ChemComp-PC1: |
-分子 #10: CHOLESTEROL
分子 | 名称: CHOLESTEROL / タイプ: ligand / ID: 10 / コピー数: 2 / 式: CLR |
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分子量 | 理論値: 386.654 Da |
Chemical component information | ![]() ChemComp-CLR: |
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
緩衝液 | pH: 7.4 |
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凍結 | 凍結剤: ETHANE |
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電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 平均電子線量: 50.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1.8 µm / 最小 デフォーカス(公称値): 1.5 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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画像解析
初期モデル | モデルのタイプ: EMDB MAP EMDB ID: |
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最終 再構成 | 解像度のタイプ: BY AUTHOR / 解像度: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 使用した粒子像数: 463727 |
初期 角度割当 | タイプ: MAXIMUM LIKELIHOOD |
最終 角度割当 | タイプ: MAXIMUM LIKELIHOOD |