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- PDB-8k8e: Human gamma-secretase in complex with a substrate mimetic -

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Entry
Database: PDB / ID: 8k8e
TitleHuman gamma-secretase in complex with a substrate mimetic
Components
  • (Gamma-secretase subunit ...) x 2
  • Nicastrin
  • Presenilin-1
  • ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2
KeywordsMEMBRANE PROTEIN / Complex / protease / substrate mimetic
Function / homology
Function and homology information


Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / 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 ...Cajal-Retzius cell differentiation / positive regulation of L-glutamate import across plasma membrane / amyloid precursor protein biosynthetic process / positive regulation of endopeptidase activity / 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 / synaptic vesicle targeting / 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 / metanephros development / endoplasmic reticulum calcium ion homeostasis / brain morphogenesis / amyloid precursor protein metabolic process / regulation of long-term synaptic potentiation / embryonic limb morphogenesis / regulation of postsynapse organization / locomotion / astrocyte activation involved in immune response / G protein-coupled dopamine receptor signaling pathway / cell fate specification / regulation of canonical Wnt signaling pathway / regulation of synaptic vesicle cycle / myeloid cell homeostasis / aggresome / skeletal system morphogenesis / Hydrolases; Acting on peptide bonds (peptidases); Aspartic endopeptidases / growth factor receptor binding / Golgi cisterna membrane / azurophil granule membrane / positive regulation of amyloid fibril formation / dorsal/ventral neural tube patterning / glutamate receptor signaling pathway / amyloid precursor protein catabolic process / amyloid-beta formation / 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 / positive regulation of receptor recycling / membrane protein ectodomain proteolysis / adult behavior / 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 / endopeptidase activator activity / negative regulation of ubiquitin-dependent protein catabolic process / somitogenesis / neuron development / Nuclear signaling by ERBB4 / hematopoietic progenitor cell differentiation / autophagosome assembly / regulation of synaptic transmission, glutamatergic / calcium ion homeostasis / Degradation of the extracellular matrix / Notch signaling pathway / rough endoplasmic reticulum / neuron projection maintenance / astrocyte activation / NOTCH2 Activation and Transmission of Signal to the Nucleus / cellular response to calcium ion / epithelial cell proliferation / NRIF signals cell death from the nucleus / cerebellum development / positive regulation of glycolytic process / thymus development / Activated NOTCH1 Transmits Signal to the Nucleus / dendritic shaft / post-embryonic development / PDZ domain binding / neuromuscular junction / apoptotic signaling pathway / NOTCH3 Activation and Transmission of Signal to the Nucleus / neuron cellular homeostasis / cell-cell adhesion / protein processing
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
CHOLESTEROL / 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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsShi, Y.G. / Zhou, R. / Wolfe, M.S.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81920108015 China
CitationJournal: Cell Rep / Year: 2024
Title: Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes.
Authors: Sujan Devkota / Rui Zhou / Vaishnavi Nagarajan / Masato Maesako / Hung Do / Arshad Noorani / Caitlin Overmeyer / Sanjay Bhattarai / Justin T Douglas / Anita Saraf / Yinglong Miao / Brian D ...Authors: Sujan Devkota / Rui Zhou / Vaishnavi Nagarajan / Masato Maesako / Hung Do / Arshad Noorani / Caitlin Overmeyer / Sanjay Bhattarai / Justin T Douglas / Anita Saraf / Yinglong Miao / Brian D Ackley / Yigong Shi / Michael S Wolfe /
Abstract: Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide ...Mutations that cause familial Alzheimer's disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process-not the products-of γ-secretase cleavage of substrates in FAD pathogenesis.
History
DepositionJul 29, 2023Deposition site: PDBJ / Processing site: PDBC
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Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / em_admin / em_entity_assembly / em_software / entity / entity_poly / entity_poly_seq / pdbx_entity_instance_feature / pdbx_entry_details / pdbx_modification_feature / pdbx_poly_seq_scheme / struct_conf / struct_conn / struct_ref_seq
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_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.group_PDB / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.label_seq_id / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.pdbx_synonyms / _chem_comp.type / _em_admin.last_update / _em_entity_assembly.entity_id_list / _em_software.name / _entity.formula_weight / _entity.pdbx_description / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly.pdbx_strand_id / _entity_poly_seq.mon_id / _pdbx_entity_instance_feature.auth_comp_id / _pdbx_entity_instance_feature.comp_id / _pdbx_entry_details.has_protein_modification / _pdbx_poly_seq_scheme.auth_mon_id / _pdbx_poly_seq_scheme.auth_seq_num / _pdbx_poly_seq_scheme.mon_id / _pdbx_poly_seq_scheme.pdb_mon_id / _pdbx_poly_seq_scheme.pdb_strand_id / _struct_conf.beg_auth_asym_id / _struct_conf.beg_auth_comp_id / _struct_conf.beg_auth_seq_id / _struct_conf.beg_label_comp_id / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_asym_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_seq_id / _struct_conf.pdbx_PDB_helix_length / _struct_ref_seq.pdbx_strand_id
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Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _em_admin.last_update / _em_entity_assembly.entity_id_list / _em_software.name / _entity.formula_weight / _entity.pdbx_description / _entity_poly.pdbx_seq_one_letter_code / _entity_poly.pdbx_seq_one_letter_code_can / _entity_poly.pdbx_strand_id / _struct_ref_seq.pdbx_strand_id
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Nicastrin
B: Presenilin-1
C: Gamma-secretase subunit APH-1A
D: Gamma-secretase subunit PEN-2
H: ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,32417
Polymers174,1175
Non-polymers4,20612
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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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) / Gene: NCSTN, KIAA0253, UNQ1874/PRO4317 / 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) / Gene: PSEN1, AD3, PS1, PSNL1 / 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) / Gene: APH1A, PSF, CGI-78, UNQ579/PRO1141 / 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) / Gene: PSENEN, PEN2, MDS033 / Production host: Homo sapiens (human) / References: UniProt: Q9NZ42

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Protein/peptide , 1 types, 1 molecules H

#5: Protein/peptide ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2


Mass: 1864.298 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Sugars , 3 types, 8 molecules

#6: 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.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Polysaccharide beta-D-mannopyranose-(1-3)-[beta-D-mannopyranose-(1-6)]beta-D-mannopyranose


Type: oligosaccharide / Mass: 504.438 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3[DManpb1-6]DManpb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,3,2/[a1122h-1b_1-5]/1-1-1/a3-b1_a6-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}LINUCSPDB-CARE
#8: 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.: 6 / Source method: obtained synthetically / 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 , 2 types, 4 molecules

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


Mass: 790.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#10: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestY
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 / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 349532 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00411174
ELECTRON MICROSCOPYf_angle_d0.60315241
ELECTRON MICROSCOPYf_dihedral_angle_d9.5311712
ELECTRON MICROSCOPYf_chiral_restr0.0971811
ELECTRON MICROSCOPYf_plane_restr0.0041840

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