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- EMDB-40480: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Micr... -

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Basic information

Entry
Database: EMDB / ID: EMD-40480
TitleTUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
Map data
Sample
  • Complex: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
    • Protein or peptide: Tubulin alpha-1A chain
    • Protein or peptide: Tubulin beta-4B chain
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
KeywordsCilia / Axoneme / Microtubule / STRUCTURAL PROTEIN
Function / homology
Function and homology information


Post-chaperonin tubulin folding pathway / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / organelle transport along microtubule / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / forebrain morphogenesis / Intraflagellar transport / Sealing of the nuclear envelope (NE) by ESCRT-III ...Post-chaperonin tubulin folding pathway / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / organelle transport along microtubule / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / forebrain morphogenesis / Intraflagellar transport / Sealing of the nuclear envelope (NE) by ESCRT-III / cerebellar cortex morphogenesis / dentate gyrus development / Formation of tubulin folding intermediates by CCT/TriC / glial cell differentiation / neuron projection arborization / flagellated sperm motility / Gap junction assembly / Prefoldin mediated transfer of substrate to CCT/TriC / Kinesins / centrosome cycle / Assembly and cell surface presentation of NMDA receptors / COPI-independent Golgi-to-ER retrograde traffic / response to L-glutamate / pyramidal neuron differentiation / COPI-dependent Golgi-to-ER retrograde traffic / smoothened signaling pathway / natural killer cell mediated cytotoxicity / regulation of synapse organization / startle response / MHC class I protein binding / motor behavior / Recycling pathway of L1 / locomotory exploration behavior / response to tumor necrosis factor / microtubule polymerization / response to mechanical stimulus / RHO GTPases activate IQGAPs / sperm flagellum / microtubule-based process / intercellular bridge / Hedgehog 'off' state / Activation of AMPK downstream of NMDARs / COPI-mediated anterograde transport / condensed chromosome / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / homeostasis of number of cells within a tissue / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / cellular response to calcium ion / Resolution of Sister Chromatid Cohesion / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / adult locomotory behavior / AURKA Activation by TPX2 / Translocation of SLC2A4 (GLUT4) to the plasma membrane / intracellular protein transport / neuromuscular junction / RHO GTPases Activate Formins / synapse organization / PKR-mediated signaling / visual learning / recycling endosome / cerebral cortex development / structural constituent of cytoskeleton / Aggrephagy / microtubule cytoskeleton organization / memory / cytoplasmic ribonucleoprotein granule / The role of GTSE1 in G2/M progression after G2 checkpoint / Separation of Sister Chromatids / neuron migration / HCMV Early Events / Regulation of PLK1 Activity at G2/M Transition / mitotic spindle / azurophil granule lumen / unfolded protein binding / extracellular vesicle / mitotic cell cycle / double-stranded RNA binding / microtubule cytoskeleton / neuron apoptotic process / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / gene expression / microtubule / cytoskeleton / hydrolase activity / cilium / protein heterodimerization activity / cell division / GTPase activity / Neutrophil degranulation / GTP binding / protein-containing complex binding / structural molecule activity / extracellular exosome / extracellular region
Similarity search - Function
Tubulin-beta mRNA autoregulation signal. / Alpha tubulin / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain ...Tubulin-beta mRNA autoregulation signal. / Alpha tubulin / Beta tubulin, autoregulation binding site / Beta tubulin / Tubulin / Tubulin, C-terminal / Tubulin C-terminal domain / Tubulin, conserved site / Tubulin subunits alpha, beta, and gamma signature. / Tubulin/FtsZ family, C-terminal domain / Tubulin/FtsZ-like, C-terminal domain / Tubulin/FtsZ, C-terminal / Tubulin/FtsZ, 2-layer sandwich domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ family, GTPase domain / Tubulin/FtsZ, GTPase domain / Tubulin/FtsZ, GTPase domain superfamily
Similarity search - Domain/homology
Tubulin beta-4B chain / Tubulin alpha-1A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsAnderson JR / Gui M / Brown A
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)5R01GM141109 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)5F30HL162128 United States
The Pew Charitable Trusts United States
CitationJournal: Science / Year: 2024
Title: Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
Authors: Daniel O Dodd / Sabrina Mechaussier / Patricia L Yeyati / Fraser McPhie / Jacob R Anderson / Chen Jing Khoo / Amelia Shoemark / Deepesh K Gupta / Thomas Attard / Maimoona A Zariwala / Marie ...Authors: Daniel O Dodd / Sabrina Mechaussier / Patricia L Yeyati / Fraser McPhie / Jacob R Anderson / Chen Jing Khoo / Amelia Shoemark / Deepesh K Gupta / Thomas Attard / Maimoona A Zariwala / Marie Legendre / Diana Bracht / Julia Wallmeier / Miao Gui / Mahmoud R Fassad / David A Parry / Peter A Tennant / Alison Meynert / Gabrielle Wheway / Lucas Fares-Taie / Holly A Black / Rana Mitri-Frangieh / Catherine Faucon / Josseline Kaplan / Mitali Patel / Lisa McKie / Roly Megaw / Christos Gatsogiannis / Mai A Mohamed / Stuart Aitken / Philippe Gautier / Finn R Reinholt / Robert A Hirst / Chris O'Callaghan / Ketil Heimdal / Mathieu Bottier / Estelle Escudier / Suzanne Crowley / Maria Descartes / Ethylin W Jabs / Priti Kenia / Jeanne Amiel / Giacomo Maria Bacci / Claudia Calogero / Viviana Palazzo / Lucia Tiberi / Ulrike Blümlein / Andrew Rogers / Jennifer A Wambach / Daniel J Wegner / Anne B Fulton / Margaret Kenna / Margaret Rosenfeld / Ingrid A Holm / Alan Quigley / Emma A Hall / Laura C Murphy / Diane M Cassidy / Alex von Kriegsheim / / / / Jean-François Papon / Laurent Pasquier / Marlène S Murris / James D Chalmers / Claire Hogg / Kenneth A Macleod / Don S Urquhart / Stefan Unger / Timothy J Aitman / Serge Amselem / Margaret W Leigh / Michael R Knowles / Heymut Omran / Hannah M Mitchison / Alan Brown / Joseph A Marsh / Julie P I Welburn / Shih-Chieh Ti / Amjad Horani / Jean-Michel Rozet / Isabelle Perrault / Pleasantine Mill /
Abstract: Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context- ...Tubulin, one of the most abundant cytoskeletal building blocks, has numerous isotypes in metazoans encoded by different conserved genes. Whether these distinct isotypes form cell type- and context-specific microtubule structures is poorly understood. Based on a cohort of 12 patients with primary ciliary dyskinesia as well as mouse mutants, we identified and characterized variants in the isotype that specifically perturbed centriole and cilium biogenesis. Distinct variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner. Structure-function studies revealed that different TUBB4B variants disrupted distinct tubulin interfaces, thereby enabling stratification of patients into three classes of ciliopathic diseases. These findings show that specific tubulin isotypes have distinct and nonredundant subcellular functions and establish a link between tubulinopathies and ciliopathies.
History
DepositionApr 13, 2023-
Header (metadata) releaseMay 1, 2024-
Map releaseMay 1, 2024-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_40480.png

Downloads & links

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Map

FileDownload / File: emd_40480.map.gz / Format: CCP4 / Size: 512 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.37 Å/pix.
x 512 pix.
= 701.44 Å		1.37 Å/pix.
x 512 pix.
= 701.44 Å		1.37 Å/pix.
x 512 pix.
= 701.44 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.37 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0277
Minimum - Maximum-0.07355815 - 0.14342566
Average (Standard dev.)0.000022679458 (±0.0014845117)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions512512512
Spacing512512512
CellA=B=C: 701.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_40480_msk_1.map
Projections & Slices
AxesZYX

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Histogram

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Half map: #2

Fileemd_40480_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_40480_half_map_2.map
Projections & Slices
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Sample components

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Entire : TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Micr...

EntireName: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
Components
  • Complex: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
    • Protein or peptide: Tubulin alpha-1A chain
    • Protein or peptide: Tubulin beta-4B chain
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE

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Supramolecule #1: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Micr...

SupramoleculeName: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.6 KDa

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Macromolecule #1: Tubulin alpha-1A chain

MacromoleculeName: Tubulin alpha-1A chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.188441 KDa
SequenceString: MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK HVPRAVFVDL EPTVIDEVRT GTYRQLFHP EQLITGKEDA ANNYARGHYT IGKEIIDLVL DRIRKLADQC TGLQGFLVFH SFGGGTGSGF TSLLMERLSV D YGKKSKLE ...String:
MRECISIHVG QAGVQIGNAC WELYCLEHGI QPDGQMPSDK TIGGGDDSFN TFFSETGAGK HVPRAVFVDL EPTVIDEVRT GTYRQLFHP EQLITGKEDA ANNYARGHYT IGKEIIDLVL DRIRKLADQC TGLQGFLVFH SFGGGTGSGF TSLLMERLSV D YGKKSKLE FSIYPAPQVS TAVVEPYNSI LTTHTTLEHS DCAFMVDNEA IYDICRRNLD IERPTYTNLN RLIGQIVSSI TA SLRFDGA LNVDLTEFQT NLVPYPRIHF PLATYAPVIS AEKAYHEQLS VAEITNACFE PANQMVKCDP RHGKYMACCL LYR GDVVPK DVNAAIATIK TKRTIQFVDW CPTGFKVGIN YQPPTVVPGG DLAKVQRAVC MLSNTTAIAE AWARLDHKFD LMYA KRAFV HWYVGEGMEE GEFSEAREDM AALEKDYEEV GVDSVEGEGE EEGEEY

UniProtKB: Tubulin alpha-1A chain

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Macromolecule #2: Tubulin beta-4B chain

MacromoleculeName: Tubulin beta-4B chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.877824 KDa
SequenceString: MREIVHLQAG QCGNQIGAKF WEVISDEHGI DPTGTYHGDS DLQLERINVY YNEATGGKYV PRAVLVDLEP GTMDSVRSGP FGQIFRPDN FVFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKEAESCDC LQGFQLTHSL GGGTGSGMGT LLISKIREEY P DRIMNTFS ...String:
MREIVHLQAG QCGNQIGAKF WEVISDEHGI DPTGTYHGDS DLQLERINVY YNEATGGKYV PRAVLVDLEP GTMDSVRSGP FGQIFRPDN FVFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKEAESCDC LQGFQLTHSL GGGTGSGMGT LLISKIREEY P DRIMNTFS VVPSPKVSDT VVEPYNATLS VHQLVENTDE TYCIDNEALY DICFRTLKLT TPTYGDLNHL VSATMSGVTT CL RFPGQLN ADLRKLAVNM VPFPRLHFFM PGFAPLTSRG SQQYRALTVP ELTQQMFDAK NMMAACDPRH GRYLTVAAVF RGR MSMKEV DEQMLNVQNK NSSYFVEWIP NNVKTAVCDI PPRGLKMSAT FIGNSTAIQE LFKRISEQFT AMFRRKAFLH WYTG EGMDE MEFTEAESNM NDLVSEYQQY QDATAEEEGE FEEEAEEEVA

UniProtKB: Tubulin beta-4B chain

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Macromolecule #3: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: GTP
Molecular weightTheoretical: 523.18 Da
Chemical component information

ChemComp-GTP:
GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying molecule*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.3
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN 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: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 64000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: EMDB MAP
EMDB ID:

26624

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 208558
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
FSC plot (resolution estimation)

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