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- EMDB-10793: Cryo-EM structure of the Full-length disease type human Huntingtin -

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Basic information

Entry
Database: EMDB / ID: EMD-10793
TitleCryo-EM structure of the Full-length disease type human Huntingtin
Map data
Sample
  • Organelle or cellular component: Full-length human disease-type huntingtin
    • Protein or peptide: Huntingtin
Function / homology
Function and homology information


regulation of cAMP-dependent protein kinase activity / regulation of phosphoprotein phosphatase activity / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / microtubule-based transport / vocal learning / regulation of CAMKK-AMPK signaling cascade / positive regulation of mitophagy / profilin binding / vesicle transport along microtubule / positive regulation of cilium assembly ...regulation of cAMP-dependent protein kinase activity / regulation of phosphoprotein phosphatase activity / positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity / microtubule-based transport / vocal learning / regulation of CAMKK-AMPK signaling cascade / positive regulation of mitophagy / profilin binding / vesicle transport along microtubule / positive regulation of cilium assembly / presynaptic cytosol / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / positive regulation of aggrephagy / postsynaptic cytosol / positive regulation of lipophagy / dynein intermediate chain binding / beta-tubulin binding / Golgi organization / dynactin binding / establishment of mitotic spindle orientation / Regulation of MECP2 expression and activity / autophagosome / inclusion body / heat shock protein binding / centriole / negative regulation of extrinsic apoptotic signaling pathway / protein destabilization / cytoplasmic vesicle membrane / kinase binding / p53 binding / late endosome / transmembrane transporter binding / early endosome / positive regulation of apoptotic process / axon / dendrite / apoptotic process / perinuclear region of cytoplasm / Golgi apparatus / endoplasmic reticulum / protein-containing complex / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 / Huntingtin, C-terminal HEAT ...Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 / Huntingtin, C-terminal HEAT / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 18.2 Å
AuthorsJung T / Tamo G / Dal Perraro M / Hebert H / Song J
Funding support Korea, Republic Of, 2 items
OrganizationGrant numberCountry
National Research Foundation (NRF, Korea)2016-K1A1A2912057 Korea, Republic Of
National Research Foundation (NRF, Korea)2016R1A2B3006293 Korea, Republic Of
CitationJournal: Structure / Year: 2020
Title: The Polyglutamine Expansion at the N-Terminal of Huntingtin Protein Modulates the Dynamic Configuration and Phosphorylation of the C-Terminal HEAT Domain.
Authors: Taeyang Jung / Baehyun Shin / Giorgio Tamo / Hyeongju Kim / Ravi Vijayvargia / Alexander Leitner / Maria J Marcaida / Juan Astorga-Wells / Roy Jung / Ruedi Aebersold / Matteo Dal Peraro / ...Authors: Taeyang Jung / Baehyun Shin / Giorgio Tamo / Hyeongju Kim / Ravi Vijayvargia / Alexander Leitner / Maria J Marcaida / Juan Astorga-Wells / Roy Jung / Ruedi Aebersold / Matteo Dal Peraro / Hans Hebert / Ihn Sik Seong / Ji-Joon Song /
Abstract: The polyQ expansion in huntingtin protein (HTT) is the prime cause of Huntington's disease (HD). The recent cryoelectron microscopy (cryo-EM) structure of HTT-HAP40 complex provided the structural ...The polyQ expansion in huntingtin protein (HTT) is the prime cause of Huntington's disease (HD). The recent cryoelectron microscopy (cryo-EM) structure of HTT-HAP40 complex provided the structural information on its HEAT-repeat domains. Here, we present analyses of the impact of polyQ length on the structure and function of HTT via an integrative structural and biochemical approach. The cryo-EM analysis of normal (Q23) and disease (Q78) type HTTs shows that the structures of apo HTTs significantly differ from the structure of HTT in a HAP40 complex and that the polyQ expansion induces global structural changes in the relative movements among the HTT domains. In addition, we show that the polyQ expansion alters the phosphorylation pattern across HTT and that Ser2116 phosphorylation in turn affects the global structure and function of HTT. These results provide a molecular basis for the effect of the polyQ segment on HTT structure and activity, which may be important for HTT pathology.
History
DepositionMar 24, 2020-
Header (metadata) releaseDec 16, 2020-
Map releaseDec 16, 2020-
UpdateDec 16, 2020-
Current statusDec 16, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.0058
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.0058
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6yej
  • Surface level: 0.0058
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-6yej
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_10793.png

Downloads & links

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Map

FileDownload / File: emd_10793.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.06 Å
Density
Contour LevelBy AUTHOR: 0.0058 / Movie #1: 0.0058
Minimum - Maximum-0.001497 - 0.015986
Average (Standard dev.)0.00027709795 (±0.0014874397)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-113-113-113
Dimensions240240240
Spacing240240240
CellA=B=C: 254.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z254.400254.400254.400
α/β/γ90.00090.00090.000
start NX/NY/NZ1081340
NX/NY/NZ13584349
MAP C/R/S123
start NC/NR/NS-113-113-113
NC/NR/NS240240240
D min/max/mean-0.0010.0160.000

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Supplemental data

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Sample components

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Entire : Full-length human disease-type huntingtin

EntireName: Full-length human disease-type huntingtin
Components
  • Organelle or cellular component: Full-length human disease-type huntingtin
    • Protein or peptide: Huntingtin

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Supramolecule #1: Full-length human disease-type huntingtin

SupramoleculeName: Full-length human disease-type huntingtin / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Details: A disease type huntingtin with 78 polyglutamine repeat tract
Source (natural)Organism: Homo sapiens (human)
Molecular weightExperimental: 350 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm) / Recombinant cell: Sf9 cell / Recombinant plasmid: pFASTBAC1

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Macromolecule #1: Huntingtin

MacromoleculeName: Huntingtin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 355.278719 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQ QQQQQQPPPP PPPPPPPQLP QPPPQAQPLL PQPQPPPPPP PPPPGPAVAE EPLHRPKKEL SATKKDRVNH C LTICENIV ...String:
MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQQ QQQQQQQQQ QQQQQQPPPP PPPPPPPQLP QPPPQAQPLL PQPQPPPPPP PPPPGPAVAE EPLHRPKKEL SATKKDRVNH C LTICENIV AQSVRNSPEF QKLLGIAMEL FLLCSDDAES DVRMVADECL NKVIKALMDS NLPRLQLELY KEIKKNGAPR SL RAALWRF AELAHLVRPQ KCRPYLVNLL PCLTRTSKRP EESVQETLAA AVPKIMASFG NFANDNEIKV LLKAFIANLK SSS PTIRRT AAGSAVSICQ HSRRTQYFYS WLLNVLLGLL VPVEDEHSTL LILGVLLTLR YLVPLLQQQV KDTSLKGSFG VTRK EMEVS PSAEQLVQVY ELTLHHTQHQ DHNVVTGALE LLQQLFRTPP PELLQTLTAV GGIGQLTAAK EESGGRSRSG SIVEL IAGG GSSCSPVLSR KQKGKVLLGE EEALEDDSES RSDVSSSALT ASVKDEISGE LAASSGVSTP GSAGHDIITE QPRSQH TLQ ADSVDLASCD LTSSATDGDE EDILSHSSSQ VSAVPSDPAM DLNDGTQASS PISDSSQTTT EGPDSAVTPS DSSEIVL DG TDNQYLGLQI GQPQDEDEEA TGILPDEASE AFRNSSMALQ QAHLLKNMSH CRQPSDSSVD KFVLRDEATE PGDQENKP C RIKGDIGQST DDDSAPLVHC VRLLSASFLL TGGKNVLVPD RDVRVSVKAL ALSCVGAAVA LHPESFFSKL YKVPLDTTE YPEEQYVSDI LNYIDHGDPQ VRGATAILCG TLICSILSRS RFHVGDWMGT IRTLTGNTFS LADCIPLLRK TLKDESSVTC KLACTAVRN CVMSLCSSSY SELGLQLIID VLTLRNSSYW LVRTELLETL AEIDFRLVSF LEAKAENLHR GAHHYTGLLK L QERVLNNV VIHLLGDEDP RVRHVAAASL IRLVPKLFYK CDQGQADPVV AVARDQSSVY LKLLMHETQP PSHFSVSTIT RI YRGYNLL PSITDVTMEN NLSRVIAAVS HELITSTTRA LTFGCCEALC LLSTAFPVCI WSLGWHCGVP PLSASDESRK SCT VGMATM ILTLLSSAWF PLDLSAHQDA LILAGNLLAA SAPKSLRSSW ASEEEANPAA TKQEEVWPAL GDRALVPMVE QLFS HLLKV INICAHVLDD VAPGPAIKAA LPSLTNPPSL SPIRRKGKEK EPGEQASVPL SPKKGSEASA ASRQSDTSGP VTTSK SSSL GSFYHLPSYL RLHDVLKATH ANYKVTLDLQ NSTEKFGGFL RSALDVLSQI LELATLQDIG KCVEEILGYL KSCFSR EPM MATVCVQQLL KTLFGTNLAS QFDGLSSNPS KSQGRAQRLG SSSVRPGLYH YCFMAPYTHF TQALADASLR NMVQAEQ EN DTSGWFDVLQ KVSTQLKTNL TSVTKNRADK NAIHNHIRLF EPLVIKALKQ YTTTTCVQLQ KQVLDLLAQL VQLRVNYC L LDSDQVFIGF VLKQFEYIEV GQFRESEAII PNIFFFLVLL SYERYHSKQI IGIPKIIQLC DGIMASGRKA VTHAIPALQ PIVHDLFVLR GTNKADAGKE LETQKEVVVS MLLRLIQYHQ VLEMFILVLQ QCHKENEDKW KRLSRQIADI ILPMLAKQQM HIDSHEALG VLNTLFEILA PSSLRPVDML LRSMFVTPNT MASVSTVQLW ISGILAILRV LISQSTEDIV LSRIQELSFS P YLISCTVI NRLRDGDSTS TLEEHSEGKQ IKNLPEETFS RFLLQLVGIL LEDIVTKQLK VEMSEQQHTF YCQELGTLLM CL IHIFKSG MFRRITAAAT RLFRSDGCGG SFYTLDSLNL RARSMITTHP ALVLLWCQIL LLVNHTDYRW WAEVQQTPKR HSL SSTKLL SPQMSGEEED SDLAAKLGMC NREIVRRGAL ILFCDYVCQN LHDSEHLTWL IVNHIQDLIS LSHEPPVQDF ISAV HRNSA ASGLFIQAIQ SRCENLSTPT MLKKTLQCLE GIHLSQSGAV LTLYVDRLLC TPFRVLARMV DILACRRVEM LLAAN LQSS MAQLPMEELN RIQEYLQSSG LAQRHQRLYS LLDRFRLSTM QDSLSPSPPV SSHPLDGDGH VSLETVSPDK DWYVHL VKS QCWTRSDSAL LEGAELVNRI PAEDMNAFMM NSEFNLSLLA PCLSLGMSEI SGGQKSALFE AAREVTLARV SGTVQQL PA VHHVFQPELP AEPAAYWSKL NDLFGDAALY QSLPTLARAL AQYLVVVSKL PSHLHLPPEK EKDIVKFVVA TLEALSWH L IHEQIPLSLD LQAGLDCCCL ALQLPGLWSV VSSTEFVTHA CSLIHCVHFI LEAVAVQPGE QLLSPERRTN TPKAISEEE EEVDPNTQNP KYITAACEMV AEMVESLQSV LALGHKRNSG VPAFLTPLLR NIIISLARLP LVNSYTRVPP LVWKLGWSPK PGGDFGTAF PEIPVEFLQE KEVFKEFIYR INTLGWTSRT QFEETWATLL GVLVTQPLVM EQEESPPEED TERTQINVLA V QAITSLVL SAMTVPVAGN PAVSCLEQQP RNKPLKALDT RFGRKLSIIR GIVEQEIQAM VSKRENIATH HLYQAWDPVP SL SPATTGA LISHEKLLLQ INPERELGSM SYKLGQVSIH SVWLGNSITP LREEEWDEEE EEEADAPAPS SPPTSPVNSR KHR AGVDIH SCSQFLLELY SRWILPSSSA RRTPAILISE VVRSLLVVSD LFTERNQFEL MYVTLTELRR VHPSEDEILA QYLV PATCK AAAVLGMDKA VAEPVSRLLE STLRSSHLPS RVGALHGVLY VLECDLLDDT AKQLIPVISD YLLSNLKGIA HCVNI HSQQ HVLVMCATAF YLIENYPLDV GPEFSASIIQ MCGVMLSGSE ESTPSIIYHC ALRGLERLLL SEQLSRLDAE SLVKLS VDR VNVHSPHRAM AALGLMLTCM YTGKEKVSPG RTSDPNPAAP DSESVIVAME RVSVLFDRIR KGFPCEARVV ARILPQF LD DFFPPQDIMN KVIGEFLSNQ QPYPQFMATV VYKVFQTLHS TGQSSMVRDW VMLSLSNFTQ RAPVAMATWS LSCFFVSA S TSPWVAAILP HVISRMGKLE QVDVNLFCLV ATDFYRHQIE EELDRRAFQS VLEVVAAPGS PYHRLLTCLR NVHKVTTC

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.08 mg/mL
BufferpH: 7.5
Component:
ConcentrationFormulaName
150.0 mMNaClSodium chlorideSodium Chloride
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 300 / Support film - Material: GRAPHENE OXIDE / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 288 K / Instrument: FEI VITROBOT MARK II / Details: 30 seconds incubation 8 seconds blotting.
DetailsHTT was mixed with final 0.05% of Octyl glucoside.

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 47170 / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 0.4 µm / Nominal defocus min: 0.4 µm
Specialist opticsPhase plate: VOLTA PHASE PLATE / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 1-24 / Number real images: 1500 / Average exposure time: 6.0 sec. / Average electron dose: 33.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 45039 / Details: manual picking
CTF correctionSoftware - Name: CTFFIND (ver. 4.0)
Startup modelType of model: INSILICO MODEL / In silico model: in RELION 3D initial model building
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1)
Final 3D classificationNumber classes: 1 / Avg.num./class: 21781 / Software - Name: RELION (ver. 2.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 2.1) / Software - details: 3D auto refine
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 18.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 21781
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

6ez8


Chain - Chain ID: A / Chain - Residue range: 91-3198
RefinementProtocol: RIGID BODY FIT
Output model

PDB-6yej:
Cryo-EM structure of the Full-length disease type human Huntingtin

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