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- EMDB-25746: Octameric Twinkle Helicase Clinical Variant W315L, local refinement -

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Basic information

Entry
Database: EMDB / ID: EMD-25746
TitleOctameric Twinkle Helicase Clinical Variant W315L, local refinement
Map dataOctameric Twinkle Helicase Clinical Variant W315L, local refinement
Sample
  • Complex: local refinement of Octameric Human Twinkle Clinical Variant W315L
    • Other: Human Twinkle Helicase W315L
KeywordsHelicase / walker A / walker B / DNA binding / DNA BINDING PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsRiccio AA / Bouvette J / Borgnia MJ / Copeland WC
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)Z01 ES065078 United States
National Institutes of Health/National Institute of Environmental Health Sciences (NIH/NIEHS)Z01 ES065080 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2022
Title: Structural insight and characterization of human Twinkle helicase in mitochondrial disease.
Authors: Amanda A Riccio / Jonathan Bouvette / Lalith Perera / Matthew J Longley / Juno M Krahn / Jason G Williams / Robert Dutcher / Mario J Borgnia / William C Copeland /
Abstract: Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ...Twinkle is the mammalian helicase vital for replication and integrity of mitochondrial DNA. Over 90 Twinkle helicase disease variants have been linked to progressive external ophthalmoplegia and ataxia neuropathies among other mitochondrial diseases. Despite the biological and clinical importance, Twinkle represents the only remaining component of the human minimal mitochondrial replisome that has yet to be structurally characterized. Here, we present 3-dimensional structures of human Twinkle W315L. Employing cryo-electron microscopy (cryo-EM), we characterize the oligomeric assemblies of human full-length Twinkle W315L, define its multimeric interface, and map clinical variants associated with Twinkle in inherited mitochondrial disease. Cryo-EM, crosslinking-mass spectrometry, and molecular dynamics simulations provide insight into the dynamic movement and molecular consequences of the W315L clinical variant. Collectively, this ensemble of structures outlines a framework for studying Twinkle function in mitochondrial DNA replication and associated disease states.
History
DepositionDec 17, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_25746.png

Downloads & links

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Map

FileDownload / File: emd_25746.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationOctameric Twinkle Helicase Clinical Variant W315L, local refinement
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 400 pix.
= 423.2 Å		1.06 Å/pix.
x 400 pix.
= 423.2 Å		1.06 Å/pix.
x 400 pix.
= 423.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.058 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.221
Minimum - Maximum-0.0017959923 - 2.0428538
Average (Standard dev.)0.0011440477 (±0.023297414)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 423.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map 1

Fileemd_25746_half_map_1.map
AnnotationHalf Map 1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map 2

Fileemd_25746_half_map_2.map
AnnotationHalf Map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : local refinement of Octameric Human Twinkle Clinical Variant W315L

EntireName: local refinement of Octameric Human Twinkle Clinical Variant W315L
Components
  • Complex: local refinement of Octameric Human Twinkle Clinical Variant W315L
    • Other: Human Twinkle Helicase W315L

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Supramolecule #1: local refinement of Octameric Human Twinkle Clinical Variant W315L

SupramoleculeName: local refinement of Octameric Human Twinkle Clinical Variant W315L
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 624 KDa

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Macromolecule #1: Human Twinkle Helicase W315L

MacromoleculeName: Human Twinkle Helicase W315L / type: other / ID: 1 / Classification: other
Source (natural)Organism: Homo sapiens (human)
SequenceString: MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATE IRQYLRGHGI PFQDGHSCLR ALSPFAESSQ LKGQTGVTTS F SLFIDKTT GHFLCMTSLA EGSWEDFQAS VEGRGDGARE GFLLSKAPEF ED SEEVRRI WNRAIPLWEL ...String:
MWVLLRSGYP LRILLPLRGE WMGRRGLPRN LAPGPPRRRY RKETLQALDM PVLPVTATE IRQYLRGHGI PFQDGHSCLR ALSPFAESSQ LKGQTGVTTS F SLFIDKTT GHFLCMTSLA EGSWEDFQAS VEGRGDGARE GFLLSKAPEF ED SEEVRRI WNRAIPLWEL PDQEEVQLAD TMFGLTKVTD DTLKRFSVRY LRP ARSLVF PWFSPGGSGL RGLKLLEAKC QGDGVSYEET TIPRPSAYHN LFGL PLISR RDAEVVLTSR ELDSLALNQS TGLPTLTLPR GTTCLPPALL PYLEQ FRRI VFWLGDDLRS LEAAKLFARK LNPKRCFLVR PGDQQPRPLE ALNGGF NLS RILRTALPAW HKSIVSFRQL REEVLGELSN VEQAAGLRWS RFPDLNR IL KGHRKGELTV FTGPTGSGKT TFISEYALDL CSQGVNTLWG SFEISNVR L ARVMLTQFAE GRLEDQLDKY DHWADRFEDL PLYFMTFHGQ QSIRTVIDT MQHAVYVYDI CHVIIDNLQF MMGHEQLSTD RIAAQDYIIG VFRKFATDNN CHVTLVIHP RKEDDDKELQ TASIFGSAKA SQEADNVLIL QDRKLVTGPG K RYLQVSKN RFDGDVGVFP LEFNKNSLTF SIPPKNKARL KKIKDDTGPV AK KPSSGKK GATTQNSEIC SGQAPTPDQP DTSKRSKAAA LEHHHHHH
Recombinant expressionOrganism: Escherichia coli (E. coli)

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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

Concentration1.2 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 441584
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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