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- EMDB-3984: Human Huntingtin-HAP40 complex structure -

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Basic information

Entry
Database: EMDB / ID: EMD-3984
TitleHuman Huntingtin-HAP40 complex structure
Map dataHuntingtin-HAP40 complex
Sample
  • Complex: Huntingtin-HAP40 complex
    • Protein or peptide: Huntingtin
    • Protein or peptide: Factor VIII intron 22 protein
Function / homology
Function and homology information


vesicle cytoskeletal trafficking / 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 / negative regulation of proteasomal protein catabolic process / positive regulation of mitophagy / profilin binding ...vesicle cytoskeletal trafficking / 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 / negative regulation of proteasomal protein catabolic process / 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 / nuclear body / 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
Factor VIII intron 22 protein / Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 ...Factor VIII intron 22 protein / Huntingtin / Huntingtin, middle-repeat / Huntingtin family / : / : / : / Huntingtin, N-terminal HEAT / Huntingtin, bridge / Huntingtin, N-terminal HEAT 1 / Huntingtin, C-terminal HEAT / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / Armadillo-type fold
Similarity search - Domain/homology
40-kDa huntingtin-associated protein / Huntingtin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsGuo Q / Bin H / Cheng J / Pfeifer G / Baumeister W / Fernandez-Busnadiego R / Kochanek S
Funding support Germany, United States, 3 items
OrganizationGrant numberCountry
European CommissionFP7 GA ERC-2012-SyG_318987-ToPAG Germany
CHDI foundation Germany
CHDIA12302 United States
CitationJournal: Nature / Year: 2018
Title: The cryo-electron microscopy structure of huntingtin.
Authors: Qiang Guo / Bin Huang / Jingdong Cheng / Manuel Seefelder / Tatjana Engler / Günter Pfeifer / Patrick Oeckl / Markus Otto / Franziska Moser / Melanie Maurer / Alexander Pautsch / Wolfgang ...Authors: Qiang Guo / Bin Huang / Jingdong Cheng / Manuel Seefelder / Tatjana Engler / Günter Pfeifer / Patrick Oeckl / Markus Otto / Franziska Moser / Melanie Maurer / Alexander Pautsch / Wolfgang Baumeister / Rubén Fernández-Busnadiego / Stefan Kochanek /
Abstract: Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the ...Huntingtin (HTT) is a large (348 kDa) protein that is essential for embryonic development and is involved in diverse cellular activities such as vesicular transport, endocytosis, autophagy and the regulation of transcription. Although an integrative understanding of the biological functions of HTT is lacking, the large number of identified HTT interactors suggests that it serves as a protein-protein interaction hub. Furthermore, Huntington's disease is caused by a mutation in the HTT gene, resulting in a pathogenic expansion of a polyglutamine repeat at the amino terminus of HTT. However, only limited structural information regarding HTT is currently available. Here we use cryo-electron microscopy to determine the structure of full-length human HTT in a complex with HTT-associated protein 40 (HAP40; encoded by three F8A genes in humans) to an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The amino- and carboxy-terminal domains contain multiple HEAT (huntingtin, elongation factor 3, protein phosphatase 2A and lipid kinase TOR) repeats arranged in a solenoid fashion. These domains are connected by a smaller bridge domain containing different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat-like organization. HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT. These data rationalize previous biochemical results and pave the way for improved understanding of the diverse cellular functions of HTT.
History
DepositionNov 14, 2017-
Header (metadata) releaseDec 20, 2017-
Map releaseFeb 21, 2018-
UpdateDec 11, 2019-
Current statusDec 11, 2019Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6ez8
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_3984.png

Downloads & links

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Map

FileDownload / File: emd_3984.map.gz / Format: CCP4 / Size: 15.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuntingtin-HAP40 complex
Voxel sizeX=Y=Z: 1.35 Å
Density
Contour LevelBy AUTHOR: 0.07 / Movie #1: 0.07
Minimum - Maximum-0.3883469 - 0.47479543
Average (Standard dev.)0.00005575514 (±0.023309596)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions160160160
Spacing160160160
CellA=B=C: 216.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.351.351.35
M x/y/z160160160
origin x/y/z0.0000.0000.000
length x/y/z216.000216.000216.000
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS160160160
D min/max/mean-0.3880.4750.000

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Supplemental data

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Sample components

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Entire : Huntingtin-HAP40 complex

EntireName: Huntingtin-HAP40 complex
Components
  • Complex: Huntingtin-HAP40 complex
    • Protein or peptide: Huntingtin
    • Protein or peptide: Factor VIII intron 22 protein

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Supramolecule #1: Huntingtin-HAP40 complex

SupramoleculeName: Huntingtin-HAP40 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: HEK293
Molecular weightExperimental: 352 KDa

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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: 347.475375 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQPPPPPP PPPPPQLPQP PPQAQPLLPQ PQPPPPPPPP PPGPAVAEEP LHRPKKELS ATKKDRVNHC LTICENIVAQ SVRNSPEFQK LLGIAMELFL LCSDDAESDV RMVADECLNK VIKALMDSNL P RLQLELYK ...String:
MATLEKLMKA FESLKSFQQQ QQQQQQQQQQ QQQQPPPPPP PPPPPQLPQP PPQAQPLLPQ PQPPPPPPPP PPGPAVAEEP LHRPKKELS ATKKDRVNHC LTICENIVAQ SVRNSPEFQK LLGIAMELFL LCSDDAESDV RMVADECLNK VIKALMDSNL P RLQLELYK EIKKNGAPRS LRAALWRFAE LAHLVRPQKC RPYLVNLLPC LTRTSKRPEE SVQETLAAAV PKIMASFGNF AN DNEIKVL LKAFIANLKS SSPTIRRTAA GSAVSICQHS RRTQYFYSWL LNVLLGLLVP VEDEHSTLLI LGVLLTLRYL VPL LQQQVK DTSLKGSFGV TRKEMEVSPS AEQLVQVYEL TLHHTQHQDH NVVTGALELL QQLFRTPPPE LLQTLTAVGG IGQL TAAKE ESGGRSRSGS IVELIAGGGS SCSPVLSRKQ KGKVLLGEEE ALEDDSESRS DVSSSALTAS VKDEISGELA ASSGV STPG SAGHDIITEQ PRSQHTLQAD SVDLASCDLT SSATDGDEED ILSHSSSQVS AVPSDPAMDL NDGTQASSPI SDSSQT TTE GPDSAVTPSD SSEIVLDGTD NQYLGLQIGQ PQDEDEEATG ILPDEASEAF RNSSMALQQA HLLKNMSHCR QPSDSSV DK FVLRDEATEP GDQENKPCRI KGDIGQSTDD DSAPLVHCVR LLSASFLLTG GKNVLVPDRD VRVSVKALAL SCVGAAVA L HPESFFSKLY KVPLDTTEYP EEQYVSDILN YIDHGDPQVR GATAILCGTL ICSILSRSRF HVGDWMGTIR TLTGNTFSL ADCIPLLRKT LKDESSVTCK LACTAVRNCV MSLCSSSYSE LGLQLIIDVL TLRNSSYWLV RTELLETLAE IDFRLVSFLE AKAENLHRG AHHYTGLLKL QERVLNNVVI HLLGDEDPRV RHVAAASLIR LVPKLFYKCD QGQADPVVAV ARDQSSVYLK L LMHETQPP SHFSVSTITR IYRGYNLLPS ITDVTMENNL SRVIAAVSHE LITSTTRALT FGCCEALCLL STAFPVCIWS LG WHCGVPP LSASDESRKS CTVGMATMIL TLLSSAWFPL DLSAHQDALI LAGNLLAASA PKSLRSSWAS EEEANPAATK QEE VWPALG DRALVPMVEQ LFSHLLKVIN ICAHVLDDVA PGPAIKAALP SLTNPPSLSP IRRKGKEKEP GEQASVPLSP KKGS EASAA SRQSDTSGPV TTSKSSSLGS FYHLPSYLRL HDVLKATHAN YKVTLDLQNS TEKFGGFLRS ALDVLSQILE LATLQ DIGK CVEEILGYLK SCFSREPMMA TVCVQQLLKT LFGTNLASQF DGLSSNPSKS QGRAQRLGSS SVRPGLYHYC FMAPYT HFT QALADASLRN MVQAEQENDT SGWFDVLQKV STQLKTNLTS VTKNRADKNA IHNHIRLFEP LVIKALKQYT TTTCVQL QK QVLDLLAQLV QLRVNYCLLD SDQVFIGFVL KQFEYIEVGQ FRESEAIIPN IFFFLVLLSY ERYHSKQIIG IPKIIQLC D GIMASGRKAV THAIPALQPI VHDLFVLRGT NKADAGKELE TQKEVVVSML LRLIQYHQVL EMFILVLQQC HKENEDKWK RLSRQIADII LPMLAKQQMH IDSHEALGVL NTLFEILAPS SLRPVDMLLR SMFVTPNTMA SVSTVQLWIS GILAILRVLI SQSTEDIVL SRIQELSFSP YLISCTVINR LRDGDSNSTL EEHSEGKQIK NLPEETFSRF LLQLVGILLE DIVTKQLKVE M SEQQHTFY CQELGTLLMC LIHIFKSGMF RRITAAATRL FRSDGCGGSF YTLDSLNLRA RSMITTHPAL VLLWCQILLL VN HTDYRWW AEVQQTPKRH SLSSTKLLSP QMSGEEEDSD LAAKLGMCNR EIVRRGALIL FCDYVCQNLH DSEHLTWLIV NHI QDLISL SHEPPVQDFI SAVHRNSAAS GLFIQAIQSR CENLSTPTML KKTLQCLEGI HLSQSGAVLT LYVDRLLCTP FRVL ARMVD ILACRRVEML LAANLQSSMA QLPMEELNRI QEYLQSSGLA QRHQRLYSLL DRFRLSTMQD SLSPSPPVSS HPLDG DGHV SLETVSPDKD WYVHLVKSQC WTRSDSALLE GAELVNRIPA EDMNAFMMNS EFNLSLLAPC LSLGMSEISG GQKSAL FEA AREVTLARVS GTVQQLPAVH HVFQPELPAE PAAYWSKLND LFGDAALYQS LPTLARALAQ YLVVVSKLPS HLHLPPE KE KDIVKFVVAT LEALSWHLIH EQIPLSLDLQ AGLDCCCLAL QLPGLWSVVS STEFVTHACS LIHCVHFILE AVAVQPGE Q LLSPERRTNT PKAISEEEEE VDPNTQNPKY ITAACEMVAE MVESLQSVLA LGHKRNSGVP AFLTPLLRNI IISLARLPL VNSYTRVPPL VWKLGWSPKP GGDFGTAFPE IPVEFLQEKE VFKEFIYRIN TLGWTSRTQF EETWATLLGV LVTQPLVMEQ EESPPEEDT ERTQINVLAV QAITSLVLSA MTVPVAGNPA VSCLEQQPRN KPLKALDTRF GRKLSIIRGI VEQEIQAMVS K RENIATHH LYQAWDPVPS LSPATTGALI SHEKLLLQIN PERELGSMSY KLGQVSIHSV WLGNSITPLR EEEWDEEEEE EA DAPAPSS PPTSPVNSRK HRAGVDIHSC SQFLLELYSR WILPSSSARR TPAILISEVV RSLLVVSDLF TERNQFELMY VTL TELRRV HPSEDEILAQ YLVPATCKAA AVLGMDKAVA EPVSRLLEST LRSSHLPSRV GALHGVLYVL ECDLLDDTAK QLIP VISDY LLSNLKGIAH CVNIHSQQHV LVMCATAFYL IENYPLDVGP EFSASIIQMC GVMLSGSEES TPSIIYHCAL RGLER LLLS EQLSRLDAES LVKLSVDRVN VHSPHRAMAA LGLMLTCMYT GKEKVSPGRT SDPNPAAPDS ESVIVAMERV SVLFDR IRK GFPCEARVVA RILPQFLDDF FPPQDIMNKV IGEFLSNQQP YPQFMATVVY KVFQTLHSTG QSSMVRDWVM LSLSNFT QR APVAMATWSL SCFFVSASTS PWVAAILPHV ISRMGKLEQV DVNLFCLVAT DFYRHQIEEE LDRRAFQSVL EVVAAPGS P YHRLLTCLRN VHKVTTC

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Macromolecule #2: Factor VIII intron 22 protein

MacromoleculeName: Factor VIII intron 22 protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.141879 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAAAAGLGG GGAGPGPEAG DFLARYRLVS NKLKKRFLRK PNVAEAGEQF GQLGRELRAQ ECLPYAAWCQ LAVARCQQAL FHGPGEALA LTEAARLFLR QERDARQRLV CPAAYGEPLQ AAASALGAAV RLHLELGQPA AAAALCLELA AALRDLGQPA A AAGHFQRA ...String:
MAAAAAGLGG GGAGPGPEAG DFLARYRLVS NKLKKRFLRK PNVAEAGEQF GQLGRELRAQ ECLPYAAWCQ LAVARCQQAL FHGPGEALA LTEAARLFLR QERDARQRLV CPAAYGEPLQ AAASALGAAV RLHLELGQPA AAAALCLELA AALRDLGQPA A AAGHFQRA AQLQLPQLPL AALQALGEAA SCQLLARDYT GALAVFTRMQ RLAREHGSHP VQSLPPPPPP APQPGPGATP AL PAALLPP NSGSAAPSPA ALGAFSDVLV RCEVSRVLLL LLLQPPPAKL LPEHAQTLEK YSWEAFDSHG QESSGQLPEE LFL LLQSLV MATHEKDTEA IKSLQVEMWP LLTAEQNHLL HLVLQETISP SGQGV

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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

Concentration0.5 mg/mL
BufferpH: 8
GridMaterial: GOLD / Support film - Material: GRAPHENE / Support film - topology: CONTINUOUS / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated defocus max: 3.0 µm / Calibrated defocus min: 1.4 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 32.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2.1) / Number images used: 98310

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