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- PDB-5a63: Cryo-EM structure of the human gamma-secretase complex at 3.4 ang... -

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Entry
Database: PDB / ID: 5a63
TitleCryo-EM structure of the human gamma-secretase complex at 3.4 angstrom resolution.
Components
  • (Gamma-secretase subunit ...) x 2
  • Nicastrin
  • Presenilin-1
KeywordsHYDROLASE / CRYO-EM / HUMAN GAMMA-SECRETASE / MEMBRANE PROTEIN
Function / homology
Function and homology information


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 / Noncanonical activation of NOTCH3 ...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 / 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 / growth factor receptor binding / 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 / 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 / metanephros development / 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 / smooth endoplasmic reticulum calcium ion homeostasis / regulation of canonical Wnt signaling pathway / myeloid cell homeostasis / aggresome / azurophil granule membrane / skeletal system morphogenesis / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / G protein-coupled dopamine receptor signaling pathway / glutamate receptor signaling pathway / Golgi cisterna membrane / ciliary rootlet / positive regulation of amyloid fibril formation / protein glycosylation / blood vessel development / mitochondrial transport / amyloid-beta formation / heart looping / amyloid precursor protein catabolic process / regulation of neuron projection development / positive regulation of dendritic spine development / positive regulation of receptor recycling / cerebral cortex cell migration / nuclear outer membrane / adult behavior / 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 / somitogenesis / T cell proliferation / smooth endoplasmic reticulum / hematopoietic progenitor cell differentiation / Nuclear signaling by ERBB4 / calcium ion homeostasis / NRIF signals cell death from the nucleus / regulation of synaptic transmission, glutamatergic / Activated NOTCH1 Transmits Signal to the Nucleus / rough endoplasmic reticulum / Degradation of the extracellular matrix / Notch signaling pathway / neuron projection maintenance / NOTCH3 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / thymus development / cerebellum development / positive regulation of glycolytic process / dendritic shaft / epithelial cell proliferation / post-embryonic development / PDZ domain binding / astrocyte activation / apoptotic signaling pathway / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
Similarity search - Function
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
Similarity search - Domain/homology
1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Presenilin-1 / Nicastrin / Gamma-secretase subunit APH-1A / Gamma-secretase subunit PEN-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsBai, X. / Yan, C. / Yang, G. / Lu, P. / Ma, D. / Sun, L. / Zhou, R. / Scheres, S.H.W. / Shi, Y.
CitationJournal: Nature / Year: 2015
Title: An atomic structure of human γ-secretase.
Authors: Xiao-Chen Bai / Chuangye Yan / Guanghui Yang / Peilong Lu / Dan Ma / Linfeng Sun / Rui Zhou / Sjors H W Scheres / Yigong Shi /
Abstract: Dysfunction of the intramembrane protease γ-secretase is thought to cause Alzheimer's disease, with most mutations derived from Alzheimer's disease mapping to the catalytic subunit presenilin 1 (PS1) ...Dysfunction of the intramembrane protease γ-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 γ-secretase at 3.4 Å 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 γ-secretase function.
History
DepositionJun 24, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 5, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 19, 2015Group: Database references
Revision 1.2Aug 26, 2015Group: Database references
Revision 1.3Sep 16, 2015Group: Database references / Structure summary
SupersessionDec 28, 2016ID: 4UPC
Revision 1.4Dec 28, 2016Group: Other
Revision 1.5Aug 2, 2017Group: Data collection / Category: em_image_scans / em_software / Item: _em_software.image_processing_id / _em_software.name
Revision 1.6Sep 11, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / struct_conn / struct_ref
Item: _entity.pdbx_description / _entity_name_com.name ..._entity.pdbx_description / _entity_name_com.name / _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_beg_seq_num / _entity_src_gen.pdbx_end_seq_num / _entity_src_gen.pdbx_gene_src_gene / _entity_src_gen.pdbx_gene_src_scientific_name / _entity_src_gen.pdbx_seq_type / _struct_conn.pdbx_leaving_atom_flag / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_seq_one_letter_code
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_entity_id / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list / _pdbx_unobs_or_zero_occ_atoms.label_asym_id / _pdbx_validate_close_contact.auth_asym_id_1 / _pdbx_validate_close_contact.auth_asym_id_2 / _pdbx_validate_close_contact.auth_seq_id_1 / _pdbx_validate_close_contact.auth_seq_id_2 / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag

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Structure visualization

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Assembly

Deposited unit
A: Nicastrin
B: Presenilin-1
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)177,97217
Polymers172,2534
Non-polymers5,71913
Water00
1


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

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Components

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Protein , 2 types, 2 molecules AB

#1: Protein Nicastrin


Mass: 78483.570 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q92542
#2: Protein Presenilin-1 / PS-1 / Protein S182


Mass: 52713.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: PSEN1, AD3, PS1, PSNL1 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human)
References: UniProt: P49768, Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases

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Gamma-secretase subunit ... , 2 types, 2 molecules CD

#3: Protein Gamma-secretase subunit APH-1A / APH-1a / Aph-1alpha / Presenilin-stabilization factor


Mass: 29017.943 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q96BI3
#4: Protein Gamma-secretase subunit PEN-2 / Presenilin enhancer protein 2


Mass: 12038.029 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Cell line: HEK 293F / Gene: PSENEN, PEN2, MDS033 / Cell line (production host): HEK 293F / Production host: HOMO SAPIENS (human) / References: UniProt: Q9NZ42

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Sugars , 3 types, 11 molecules

#5: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#6: Polysaccharide beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2- ...beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 910.823 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3[DManpb1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,5,4/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2-2-2/a4-b1_b4-c1_c3-d1_c6-e1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 1 types, 2 molecules

#8: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM

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Details

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: HUMAN GAMMA-SECRETASE / Type: COMPLEX
Buffer solutionName: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35 / pH: 7.4
Details: 25 MM HEPES, PH 7.4, 150 MM NACL AND AMPHIPOL A8-35
SpecimenConc.: 6 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- 85, INSTRUMENT- FEI VITROBOT MARK IV, METHOD- BLOT FOR 4 SECONDS BEFORE PLUNGING,

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Electron microscopy imaging

Experimental equipment
Model: Tecnai F30 / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI F30 / Date: Oct 2, 2014
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Calibrated magnification: 35714 X / Nominal defocus max: 3200 nm / Nominal defocus min: 700 nm / Cs: 2.7 mm
Specimen holderTemperature: 85 K
Image recordingElectron dose: 38 e/Å2 / Film or detector model: GATAN K2 (4k x 4k)
Radiation wavelengthRelative weight: 1

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Processing

EM software
IDNameVersionCategory
1CTFFIND3CTF correction
2RELION3D reconstruction
CTF correctionDetails: EACH PARTICLE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.4 Å / Num. of particles: 159549
Magnification calibration: CROSS- -CORRELATION DENSITIES WITHIN SPHERICAL SHELL
Details: SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3061. (DEPOSITION ID: 13527).
Symmetry type: POINT
RefinementHighest resolution: 3.4 Å
Refinement stepCycle: LAST / Highest resolution: 3.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9646 0 357 0 10003

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