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- PDB-4uis: The cryoEM structure of human gamma-Secretase complex -

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Basic information

Entry
Database: PDB / ID: 4uis
TitleThe cryoEM structure of human gamma-Secretase complex
Components
  • (GAMMA-SECRETASE) x 4
  • LYSOZYME
KeywordsHYDROLASE / GAMMA-SECRETASE
Function / homology
Function and homology information


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / 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 ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / gamma-secretase complex / aspartic endopeptidase activity, intramembrane cleaving / 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 / : / : / Notch receptor processing / positive regulation of coagulation / negative regulation of axonogenesis / membrane protein intracellular domain proteolysis / short-term synaptic potentiation / skin morphogenesis / choline transport / T cell activation involved in immune response / central nervous system myelination / NOTCH4 Activation and Transmission of Signal to the Nucleus / ciliary rootlet / neural retina development / regulation of resting membrane potential / Regulated proteolysis of p75NTR / L-glutamate import across plasma membrane / myeloid dendritic cell differentiation / endoplasmic reticulum calcium ion homeostasis / brain morphogenesis / amyloid precursor protein metabolic process / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / locomotion / cell fate specification / astrocyte activation involved in immune response / regulation of postsynapse organization / regulation of synaptic vesicle cycle / myeloid cell homeostasis / regulation of canonical Wnt signaling pathway / G protein-coupled dopamine receptor signaling pathway / aggresome / skeletal system morphogenesis / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / growth factor receptor binding / azurophil granule membrane / positive regulation of amyloid fibril formation / dorsal/ventral neural tube patterning / glutamate receptor signaling pathway / amyloid-beta formation / amyloid precursor protein catabolic process / mitochondrial transport / blood vessel development / heart looping / regulation of neuron projection development / positive regulation of dendritic spine development / cerebral cortex cell migration / smooth endoplasmic reticulum / membrane protein ectodomain proteolysis / adult behavior / positive regulation of receptor recycling / nuclear outer membrane / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of apoptotic signaling pathway / EPH-ephrin mediated repulsion of cells / T cell proliferation / somitogenesis / negative regulation of ubiquitin-dependent protein catabolic process / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / neuron development / viral release from host cell by cytolysis / endopeptidase activator activity / autophagosome assembly / regulation of synaptic transmission, glutamatergic / calcium ion homeostasis / Degradation of the extracellular matrix / Notch signaling pathway / peptidoglycan catabolic process / rough endoplasmic reticulum / neuron projection maintenance / epithelial cell proliferation / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / astrocyte activation / cerebellum development / NRIF signals cell death from the nucleus / thymus development / positive regulation of glycolytic process / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / post-embryonic development / PDZ domain binding / neuromuscular junction / NOTCH3 Activation and Transmission of Signal to the Nucleus / apoptotic signaling pathway / neuron cellular homeostasis / cell-cell adhesion / protein processing / sarcolemma
Similarity search - Function
Peptidase A22A, presenilin 1 / 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 ...Peptidase A22A, presenilin 1 / 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 / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / Lysozyme-like domain superfamily
Similarity search - Domain/homology
Endolysin / Endolysin / Presenilin-1 / Nicastrin
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.4 Å
AuthorsSun, L. / Zhao, L. / Yang, G. / Yan, C. / Zhou, R. / Zhou, X. / Xie, T. / Zhao, Y. / Wu, S. / Li, X. / Shi, Y.
CitationJournal: Proc Natl Acad Sci U S A / Year: 2015
Title: Structural basis of human γ-secretase assembly.
Authors: Linfeng Sun / Lingyun Zhao / Guanghui Yang / Chuangye Yan / Rui Zhou / Xiaoyuan Zhou / Tian Xie / Yanyu Zhao / Shenjie Wu / Xueming Li / Yigong Shi /
Abstract: The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ- ...The four-component intramembrane protease γ-secretase is intricately linked to the development of Alzheimer's disease. Despite recent structural advances, the transmembrane segments (TMs) of γ-secretase remain to be specifically assigned. Here we report a 3D structure of human γ-secretase at 4.32-Å resolution, determined by single-particle, electron cryomicroscopy in the presence of digitonin and with a T4 lysozyme fused to the amino terminus of presenilin 1 (PS1). The overall structure of this human γ-secretase is very similar to that of wild-type γ-secretase determined in the presence of amphipols. The 20 TMs are unambiguously assigned to the four components, revealing principles of subunit assembly. Within the transmembrane region, PS1 is centrally located, with its amino-terminal fragment (NTF) packing against Pen-2 and its carboxyl-terminal fragment (CTF) interacting with Aph-1. The only TM of nicastrin associates with Aph-1 at the thick end of the TM horseshoe, and the extracellular domain of nicastrin directly binds Pen-2 at the thin end. TM6 and TM7 in PS1, which harbor the catalytic aspartate residues, are located on the convex side of the TM horseshoe. This structure serves as an important framework for understanding the function and mechanism of γ-secretase.
History
DepositionApr 3, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 10, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 2, 2017Group: Data collection / Category: em_software
Item: _em_software.fitting_id / _em_software.image_processing_id / _em_software.name
Revision 1.2Nov 13, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_entry_details / pdbx_initial_refinement_model / pdbx_modification_feature / pdbx_validate_polymer_linkage
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type / _pdbx_validate_polymer_linkage.dist / _pdbx_validate_polymer_linkage.label_alt_id_1 / _pdbx_validate_polymer_linkage.label_alt_id_2

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Structure visualization

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  • Deposited structure unit
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  • Simplified surface model + fitted atomic model
  • EMDB-2974
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Structure viewerMolecule:
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Assembly

Deposited unit
A: GAMMA-SECRETASE
B: GAMMA-SECRETASE
C: GAMMA-SECRETASE
D: GAMMA-SECRETASE
G: LYSOZYME


Theoretical massNumber of molelcules
Total (without water)127,3085
Polymers127,3085
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

#1: Protein GAMMA-SECRETASE


Mass: 63331.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human) / References: UniProt: Q92542*PLUS
#2: Protein GAMMA-SECRETASE


Mass: 23547.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human) / References: UniProt: P49768*PLUS
#3: Protein GAMMA-SECRETASE


Mass: 16698.539 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
#4: Protein GAMMA-SECRETASE


Mass: 5294.518 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
#5: Protein LYSOZYME


Mass: 18435.207 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): HEK 293S / Production host: HOMO SAPIENS (human)
References: UniProt: A0A097J809, UniProt: D9IEF7*PLUS, lysozyme
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: T4-LYSOZYME FUSION GAMMA- SECRETASE / Type: COMPLEX
Buffer solutionName: 0.1% DIGITONIN, 25 MM HEPES, PH 7.4, AND 150 MM NACL. / pH: 7.4
Details: 0.1% DIGITONIN, 25 MM HEPES, PH 7.4, AND 150 MM NACL.
SpecimenConc.: 4.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: HOLEY CARBON
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE
Details: VITRIFICATION 1 -- CRYOGEN- ETHANE, HUMIDITY- 100, TEMPERATURE- 277, INSTRUMENT- FEI VITROBOT MARK IV, METHOD- BLOT FOR 3 SECONDS BEFORE PLUNGING,

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Date: Dec 22, 2014
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1500 nm / Cs: 1.4 mm
Image recordingElectron dose: 4.5 e/Å2 / Film or detector model: DIRECT ELECTRON DE-12 (4k x 3k)
Image scansNum. digital images: 2000

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Processing

EM software
IDNameCategory
1UCSF Chimeramodel fitting
2RELION3D reconstruction
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.4 Å / Num. of particles: 177207 / Nominal pixel size: 1.32 Å / Actual pixel size: 1.32 Å
Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-2974. (DEPOSITION ID: 13293
Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL / Details: METHOD--FLEXIBLE
Atomic model buildingPDB-ID: 4R12

4r12


Accession code: 4R12 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 4.4 Å
Refinement stepCycle: LAST / Highest resolution: 4.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8461 0 0 0 8461

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