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- EMDB-15948: Human Mre11-Nbs1 complex -

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Entry
Database: EMDB / ID: EMD-15948
TitleHuman Mre11-Nbs1 complex
Map datamap_sharp
Sample
  • Complex: Human Mre11-Nbs1 complex
    • Protein or peptide: Double-strand break repair protein MRE11
    • Protein or peptide: Nibrin
  • Ligand: MANGANESE (II) ION
KeywordsDNA repair / complex / HYDROLASE
Function / homology
Function and homology information


telomere maintenance via telomere trimming / chromosomal region / mitochondrial double-strand break repair via homologous recombination / telomeric 3' overhang formation / Mre11 complex / blastocyst growth / meiotic DNA double-strand break formation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / BRCA1-C complex ...telomere maintenance via telomere trimming / chromosomal region / mitochondrial double-strand break repair via homologous recombination / telomeric 3' overhang formation / Mre11 complex / blastocyst growth / meiotic DNA double-strand break formation / negative regulation of telomere capping / Sensing of DNA Double Strand Breaks / BRCA1-C complex / regulation of mitotic recombination / t-circle formation / DNA double-strand break processing / single-stranded DNA endodeoxyribonuclease activity / homologous chromosome pairing at meiosis / DNA strand resection involved in replication fork processing / homologous recombination / nuclear inclusion body / 5'-3' exonuclease activity / nuclease activity / 3'-5'-DNA exonuclease activity / positive regulation of telomere maintenance / isotype switching / Cytosolic sensors of pathogen-associated DNA / Impaired BRCA2 binding to PALB2 / HDR through MMEJ (alt-NHEJ) / IRF3-mediated induction of type I IFN / mitotic G2/M transition checkpoint / reciprocal meiotic recombination / positive regulation of kinase activity / mitotic intra-S DNA damage checkpoint signaling / sister chromatid cohesion / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / regulation of DNA-templated DNA replication initiation / Resolution of D-loop Structures through Holliday Junction Intermediates / DNA duplex unwinding / HDR through Single Strand Annealing (SSA) / Impaired BRCA2 binding to RAD51 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / neuromuscular process controlling balance / neuroblast proliferation / telomere maintenance via telomerase / DNA damage response, signal transduction by p53 class mediator / positive regulation of protein autophosphorylation / 3'-5' exonuclease activity / telomere maintenance / intrinsic apoptotic signaling pathway / DNA endonuclease activity / meiotic cell cycle / replication fork / DNA damage checkpoint signaling / Nonhomologous End-Joining (NHEJ) / double-strand break repair via homologous recombination / HDR through Homologous Recombination (HRR) / G2/M DNA damage checkpoint / DNA Damage/Telomere Stress Induced Senescence / PML body / Meiotic recombination / double-strand break repair via nonhomologous end joining / double-strand break repair / Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks / site of double-strand break / manganese ion binding / Processing of DNA double-strand break ends / double-stranded DNA binding / DNA-binding transcription factor binding / DNA recombination / cell population proliferation / Regulation of TP53 Activity through Phosphorylation / chromosome, telomeric region / damaged DNA binding / Hydrolases; Acting on ester bonds / regulation of cell cycle / cadherin binding / DNA repair / DNA damage response / nucleolus / negative regulation of apoptotic process / Golgi apparatus / nucleoplasm / identical protein binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / DNA double-strand break repair protein Mre11 / Mre11, DNA-binding ...Nibrin, C-terminal / Nibrin / DNA damage repair protein Nbs1 / DNA damage repair protein Nbs1 / Nibrin, second BRCT domain / Nibrin, second BRCT domain superfamily / Second BRCT domain on Nijmegen syndrome breakage protein / Nibrin-related / DNA double-strand break repair protein Mre11 / Mre11, DNA-binding / Mre11, capping domain / Mre11 DNA-binding presumed domain / Mre11 DNA-binding presumed domain / Mre11 nuclease, N-terminal metallophosphatase domain / Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / Calcineurin-like phosphoesterase domain, ApaH type / Calcineurin-like phosphoesterase / SMAD/FHA domain superfamily / BRCA1 C Terminus (BRCT) domain / Metallo-dependent phosphatase-like / BRCT domain / BRCT domain superfamily
Similarity search - Domain/homology
Nibrin / Double-strand break repair protein MRE11
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.13 Å
AuthorsRotheneder M / Stakyte K / Bartho JD / Lammens K / Hopfner KP
Funding support Germany, 4 items
OrganizationGrant numberCountry
German Research Foundation (DFG)CRC1361 Germany
German Research Foundation (DFG)SFB1361 Germany
German Research Foundation (DFG)GRK1721 Germany
German Research Foundation (DFG)CRC1054 Germany
CitationJournal: Mol Cell / Year: 2023
Title: Cryo-EM structure of the Mre11-Rad50-Nbs1 complex reveals the molecular mechanism of scaffolding functions.
Authors: Matthias Rotheneder / Kristina Stakyte / Erik van de Logt / Joseph D Bartho / Katja Lammens / Yilan Fan / Aaron Alt / Brigitte Kessler / Christophe Jung / Wynand P Roos / Barbara ...Authors: Matthias Rotheneder / Kristina Stakyte / Erik van de Logt / Joseph D Bartho / Katja Lammens / Yilan Fan / Aaron Alt / Brigitte Kessler / Christophe Jung / Wynand P Roos / Barbara Steigenberger / Karl-Peter Hopfner /
Abstract: The DNA double-strand break repair complex Mre11-Rad50-Nbs1 (MRN) detects and nucleolytically processes DNA ends, activates the ATM kinase, and tethers DNA at break sites. How MRN can act both as ...The DNA double-strand break repair complex Mre11-Rad50-Nbs1 (MRN) detects and nucleolytically processes DNA ends, activates the ATM kinase, and tethers DNA at break sites. How MRN can act both as nuclease and scaffold protein is not well understood. The cryo-EM structure of MRN from Chaetomium thermophilum reveals a 2:2:1 complex with a single Nbs1 wrapping around the autoinhibited Mre11 nuclease dimer. MRN has two DNA-binding modes, one ATP-dependent mode for loading onto DNA ends and one ATP-independent mode through Mre11's C terminus, suggesting how it may interact with DSBs and intact DNA. MRNs two 60-nm-long coiled-coil domains form a linear rod structure, the apex of which is assembled by the two joined zinc-hook motifs. Apices from two MRN complexes can further dimerize, forming 120-nm spanning MRN-MRN structures. Our results illustrate the architecture of MRN and suggest how it mechanistically integrates catalytic and tethering functions.
History
DepositionOct 11, 2022-
Header (metadata) releaseJan 11, 2023-
Map releaseJan 11, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15948.png

Downloads & links

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Map

FileDownload / File: emd_15948.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmap_sharp
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 180 pix.
= 190.62 Å		1.06 Å/pix.
x 180 pix.
= 190.62 Å		1.06 Å/pix.
x 180 pix.
= 190.62 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.059 Å
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Contour LevelBy AUTHOR: 0.43
Minimum - Maximum-1.6267853 - 2.7838867
Average (Standard dev.)0.011651644 (±0.09531362)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 190.62 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_15948_msk_1.map
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Additional map: Map unsharpened

Fileemd_15948_additional_1.map
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Additional map: LAFTER Filtered map

Fileemd_15948_additional_2.map
AnnotationLAFTER_Filtered_map
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Half map: Half map B

Fileemd_15948_half_map_1.map
AnnotationHalf_map_B
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Half map: Half map A

Fileemd_15948_half_map_2.map
AnnotationHalf_map_A
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Sample components

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Entire : Human Mre11-Nbs1 complex

EntireName: Human Mre11-Nbs1 complex
Components
  • Complex: Human Mre11-Nbs1 complex
    • Protein or peptide: Double-strand break repair protein MRE11
    • Protein or peptide: Nibrin
  • Ligand: MANGANESE (II) ION

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Supramolecule #1: Human Mre11-Nbs1 complex

SupramoleculeName: Human Mre11-Nbs1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Human Mre11-dimer with Nbs1 C-terminal chain bound.
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Double-strand break repair protein MRE11

MacromoleculeName: Double-strand break repair protein MRE11 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: Hydrolases; Acting on ester bonds
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 84.008633 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD LFHENKPSRK TLHTCLELLR KYCMGDRPV QFEILSDQSV NFGFSKFPWV NYQDGNLNIS IPVFSIHGNN DDPTGADALC ALDILSCAGF VNHFGRSMSV E KIDISPVL ...String:
MSTADALDDE NTFKILVATD IHLGFMEKDA VRGNDTFVTL DEILRLAQEN EVDFILLGGD LFHENKPSRK TLHTCLELLR KYCMGDRPV QFEILSDQSV NFGFSKFPWV NYQDGNLNIS IPVFSIHGNN DDPTGADALC ALDILSCAGF VNHFGRSMSV E KIDISPVL LQKGSTKIAL YGLGSIPDER LYRMFVNKKV TMLRPKEDEN SWFNLFVIHQ NRSKHGSTNF IPEQFLDDFI DL VIWGHEH ECKIAPTKNE QQLFYISQPG SSVVTSLSPG EAVKKHVGLL RIKGRKMNMH KIPLHTVRQF FMEDIVLANH PDI FNPDNP KVTQAIQSFC LEKIEEMLEN AERERLGNSH QPEKPLVRLR VDYSGGFEPF SVLRFSQKFV DRVANPKDII HFFR HREQK EKTGEEINFG KLITKPSEGT TLRVEDLVKQ YFQTAEKNVQ LSLLTERGMG EAVQEFVDKE EKDAIEELVK YQLEK TQRF LKERHIDALE DKIDEEVRRF RETRQKNTNE EDDEVREAMT RARALRSQSE ESASAFSADD LMSIDLAEQM ANDSDD SIS AATNKGRGRG RGRRGGRGQN SASRGGSQRG RADTGLETST RSRNSKTAVS ASRNMSIIDA FKSTRQQPSR NVTTKNY SE VIEVDESDVE EDIFPTTSKT DQRWSSTSSS KIMSQSQVSK GVDFESSEDD DDDPFMNTSS LRRNRRSGGS LEVLFQGP D YKDDDDKGTD YKDDDDK

UniProtKB: Double-strand break repair protein MRE11

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Macromolecule #2: Nibrin

MacromoleculeName: Nibrin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.073023 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MWKLLPAAGP AGGEPYRLLT GVEYVVGRKN CAILIENDQS ISRNHAVLTA NFSVTNLSQT DEIPVLTLKD NSKYGTFVNE EKMQNGFSR TLKSGDGITF GVFGSKFRIE YEPLVACSSC LDVSGKTALN QAILQLGGFT VNNWTEECTH LVMVSVKVTI K TICALICG ...String:
MWKLLPAAGP AGGEPYRLLT GVEYVVGRKN CAILIENDQS ISRNHAVLTA NFSVTNLSQT DEIPVLTLKD NSKYGTFVNE EKMQNGFSR TLKSGDGITF GVFGSKFRIE YEPLVACSSC LDVSGKTALN QAILQLGGFT VNNWTEECTH LVMVSVKVTI K TICALICG RPIVKPEYFT EFLKAVESKK QPPQIESFYP PLDEPSIGSK NVDLSGRQER KQIFKGKTFI FLNAKQHKKL SS AVVFGGG EARLITEENE EEHNFFLAPG TCVVDTGITN SQTLIPDCQK KWIQSIMDML QRQGLRPIPE AEIGLAVIFM TTK NYCDPQ GHPSTGLKTT TPGPSLSQGV SVDEKLMPSA PVNTTTYVAD TESEQADTWD LSERPKEIKV SKMEQKFRML SQDA PTVKE SCKTSSNNNS MVSNTLAKMR IPNYQLSPTK LPSINKSKDR ASQQQQTNSI RNYFQPSTKK RERDEENQEM SSCKS ARIE TSCSLLEQTQ PATPSLWKNK EQHLSENEPV DTNSDNNLFT DTDLKSIVKN SASKSHAAEK LRSNKKREMD DVAIED EVL EQLFKDTKPE LEIDVKVQKQ EEDVNVRKRP RMDIETNDTF SDEAVPESSK ISQENEIGKK RELKEDSLWS AKEISNN DK LQDDSEMLPK KLLLTEFRSL VIKNSTSRNP SGINDDYGQL KNFKKFKKVT YPGAGKLPHI IGGSDLIAHH ARKNTELE E WLRQEMEVQN QHAKEESLAD DLFRYNPYLK RRR

UniProtKB: Nibrin

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Macromolecule #3: MANGANESE (II) ION

MacromoleculeName: MANGANESE (II) ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: MN
Molecular weightTheoretical: 54.938 Da

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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

Concentration0.29 mg/mL
BufferpH: 7
Component:
ConcentrationFormulaName
20.0 mMC8H18N2O4SHEPES
140.0 mMNaClSodium chlorideSodium chloride
5.0 mMMgCl2Magnesium chloride
1.0 mMMnCl2Manganese chloride
0.02 mMZnCl2Zinc chloride
0.2 mMC9H15O6PTCEP
2.0 mMC10H16N5O12P3SATPgS
0.05 percentC14H28O6Octyl beta-D-glucopyranoside

Details: 20 mM HEPES (pH 7.0), 140 mM NaCl, 5 mM MgCl2, 1 mM MnCl2, 0.020 mM ZnCl2, 0.2 mM TCEP, 2 mM ATPgS, plus 0.05 percent beta-OG
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 7 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 288 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 13000
Specialist opticsEnergy filter - Name: GIF Bioquantum / 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 / Number grids imaged: 3 / Number real images: 11325 / Average exposure time: 10.0 sec. / Average electron dose: 43.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 282838
FSC plot (resolution estimation)

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