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- PDB-6w5v: NPC1-NPC2 complex structure at pH 5.5 -

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Basic information

Entry
Database: PDB / ID: 6w5v
TitleNPC1-NPC2 complex structure at pH 5.5
Components(NPC intracellular cholesterol transporter ...) x 2
KeywordsTRANSPORT PROTEIN / Cholesterol Lysosome
Function / homology
Function and homology information


regulation of isoprenoid metabolic process / glycolipid transport / intracellular sterol transport / cyclodextrin metabolic process / cholesterol storage / membrane raft organization / intracellular cholesterol transport / intracellular lipid transport / sterol transport / intestinal cholesterol absorption ...regulation of isoprenoid metabolic process / glycolipid transport / intracellular sterol transport / cyclodextrin metabolic process / cholesterol storage / membrane raft organization / intracellular cholesterol transport / intracellular lipid transport / sterol transport / intestinal cholesterol absorption / LDL clearance / negative regulation of epithelial cell apoptotic process / phospholipid transport / bile acid metabolic process / programmed cell death / cholesterol transfer activity / cholesterol transport / establishment of protein localization to membrane / adult walking behavior / cholesterol efflux / lysosomal transport / cholesterol binding / cellular response to steroid hormone stimulus / negative regulation of macroautophagy / protein glycosylation / cellular response to low-density lipoprotein particle stimulus / response to cadmium ion / negative regulation of TORC1 signaling / cholesterol metabolic process / lysosomal lumen / cholesterol homeostasis / liver development / neurogenesis / macroautophagy / response to virus / autophagy / endocytosis / azurophil granule lumen / late endosome membrane / transmembrane signaling receptor activity / nuclear envelope / signaling receptor activity / virus receptor activity / gene expression / lysosome / membrane raft / response to xenobiotic stimulus / symbiont entry into host cell / lysosomal membrane / Neutrophil degranulation / perinuclear region of cytoplasm / enzyme binding / Golgi apparatus / endoplasmic reticulum / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Npc2 like, ML domain / Sterol transport protein NPC2-like / Patched SSD / Immunoglobulin-like - #770 / NPC1-like / ML domain / MD-2-related lipid-recognition domain / Niemann-Pick C1, N-terminal / : / Niemann-Pick C1 N terminus ...Npc2 like, ML domain / Sterol transport protein NPC2-like / Patched SSD / Immunoglobulin-like - #770 / NPC1-like / ML domain / MD-2-related lipid-recognition domain / Niemann-Pick C1, N-terminal / : / Niemann-Pick C1 N terminus / NPC1, middle luminal domain / Domain involved in innate immunity and lipid metabolism. / : / Sterol-sensing domain of SREBP cleavage-activation / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / Immunoglobulin E-set / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
CHOLESTEROL / NPC intracellular cholesterol transporter 1 / NPC intracellular cholesterol transporter 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsYan, N. / Qian, H.W. / Wu, X.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)DMR-1420541 United States
CitationJournal: Cell / Year: 2020
Title: Structural Basis of Low-pH-Dependent Lysosomal Cholesterol Egress by NPC1 and NPC2.
Authors: Hongwu Qian / Xuelan Wu / Ximing Du / Xia Yao / Xin Zhao / Joyce Lee / Hongyuan Yang / Nieng Yan /
Abstract: Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that ...Lysosomal cholesterol egress requires two proteins, NPC1 and NPC2, whose defects are responsible for Niemann-Pick disease type C (NPC). Here, we present systematic structural characterizations that reveal the molecular basis for low-pH-dependent cholesterol delivery from NPC2 to the transmembrane (TM) domain of NPC1. At pH 8.0, similar structures of NPC1 were obtained in nanodiscs and in detergent at resolutions of 3.6 Å and 3.0 Å, respectively. A tunnel connecting the N-terminal domain (NTD) and the transmembrane sterol-sensing domain (SSD) was unveiled. At pH 5.5, the NTD exhibits two conformations, suggesting the motion for cholesterol delivery to the tunnel. A putative cholesterol molecule is found at the membrane boundary of the tunnel, and TM2 moves toward formation of a surface pocket on the SSD. Finally, the structure of the NPC1-NPC2 complex at 4.0 Å resolution was obtained at pH 5.5, elucidating the molecular basis for cholesterol handoff from NPC2 to NPC1(NTD).
History
DepositionMar 13, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 17, 2020Provider: repository / Type: Initial release
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Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
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Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 2.1Oct 23, 2024Group: Data collection / Database references / Structure summary
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Structure visualization

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Assembly

Deposited unit
A: NPC intracellular cholesterol transporter 1
D: NPC intracellular cholesterol transporter 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)169,67220
Polymers164,0162
Non-polymers5,65618
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area8430 Å2
ΔGint50 kcal/mol
Surface area63060 Å2

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Components

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NPC intracellular cholesterol transporter ... , 2 types, 2 molecules AD

#1: Protein NPC intracellular cholesterol transporter 1 / Niemann-Pick C1 protein


Mass: 146083.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPC1 / Production host: Homo sapiens (human) / References: UniProt: O15118
#2: Protein NPC intracellular cholesterol transporter 2 / Epididymal secretory protein E1 / Human epididymis-specific protein 1 / He1 / Niemann-Pick disease ...Epididymal secretory protein E1 / Human epididymis-specific protein 1 / He1 / Niemann-Pick disease type C2 protein


Mass: 17932.600 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: NPC2, HE1 / Production host: Homo sapiens (human) / References: UniProt: P61916

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Sugars , 3 types, 15 molecules

#3: 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.: 4
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
#4: Polysaccharide beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3DGlcpNAcb1-4DGlcpNAcb1-Glycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b3-c1WURCSPDB2Glycan 1.1.0
[]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(3+1)][b-D-Manp]{}}}}LINUCSPDB-CARE
#5: 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.: 10
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, 3 molecules

#6: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O / Feature type: SUBJECT OF INVESTIGATION

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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: NPC1-NPC2 complex at pH 5.5 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.17 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenConc.: 15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: unspecified
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
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM software
IDNameCategory
4GctfCTF correction
8PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 101364 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00710956
ELECTRON MICROSCOPYf_angle_d1.31515033
ELECTRON MICROSCOPYf_dihedral_angle_d10.7566393
ELECTRON MICROSCOPYf_chiral_restr0.061733
ELECTRON MICROSCOPYf_plane_restr0.0071870

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