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- PDB-8sh7: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Micr... -

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Basic information

Entry
Database: PDB / ID: 8sh7
TitleTUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
Components
  • Tubulin alpha-1A chain
  • Tubulin beta-4B chain
KeywordsSTRUCTURAL PROTEIN / Cilia / Axoneme / Microtubule
Function / homology
Function and homology information


Post-chaperonin tubulin folding pathway / organelle transport along microtubule / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / forebrain morphogenesis / glial cell differentiation / Intraflagellar transport ...Post-chaperonin tubulin folding pathway / organelle transport along microtubule / axonemal microtubule / Cilium Assembly / cytoskeleton-dependent intracellular transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Carboxyterminal post-translational modifications of tubulin / forebrain morphogenesis / glial cell differentiation / Intraflagellar transport / neuron projection arborization / Sealing of the nuclear envelope (NE) by ESCRT-III / cerebellar cortex morphogenesis / flagellated sperm motility / Formation of tubulin folding intermediates by CCT/TriC / dentate gyrus development / Gap junction assembly / Prefoldin mediated transfer of substrate to CCT/TriC / COPI-independent Golgi-to-ER retrograde traffic / Kinesins / centrosome cycle / Assembly and cell surface presentation of NMDA receptors / pyramidal neuron differentiation / motor behavior / COPI-dependent Golgi-to-ER retrograde traffic / natural killer cell mediated cytotoxicity / response to L-glutamate / smoothened signaling pathway / regulation of synapse organization / startle response / MHC class I protein binding / locomotory exploration behavior / Recycling pathway of L1 / microtubule polymerization / sperm flagellum / response to tumor necrosis factor / RHO GTPases activate IQGAPs / microtubule-based process / intercellular bridge / Hedgehog 'off' state / response to mechanical stimulus / Activation of AMPK downstream of NMDARs / COPI-mediated anterograde transport / condensed chromosome / homeostasis of number of cells within a tissue / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / 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 / Resolution of Sister Chromatid Cohesion / cellular response to calcium ion / 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 / RHO GTPases Activate Formins / synapse organization / neuromuscular junction / visual learning / PKR-mediated signaling / recycling endosome / cerebral cortex development / structural constituent of cytoskeleton / memory / microtubule cytoskeleton organization / cytoplasmic ribonucleoprotein granule / HCMV Early Events / neuron migration / Aggrephagy / mitotic spindle / Separation of Sister Chromatids / The role of GTSE1 in G2/M progression after G2 checkpoint / azurophil granule lumen / Regulation of PLK1 Activity at G2/M Transition / unfolded protein binding / extracellular vesicle / mitotic cell cycle / double-stranded RNA binding / microtubule cytoskeleton / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / neuron apoptotic process / gene expression / microtubule / cytoskeleton / hydrolase activity / cilium / protein heterodimerization activity / cell division / GTPase activity / Neutrophil degranulation / protein-containing complex binding / GTP 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
GUANOSINE-5'-DIPHOSPHATE / GUANOSINE-5'-TRIPHOSPHATE / Tubulin beta-4B chain / Tubulin alpha-1A chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsAnderson, J.R. / Gui, M. / Brown, A.
Funding support United States, 3items
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, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: citation / citation_author ...citation / citation_author / em_admin / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tubulin alpha-1A chain
B: Tubulin beta-4B chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)101,0575
Polymers100,0662
Non-polymers9913
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Tubulin alpha-1A chain / Alpha-tubulin 3 / Tubulin B-alpha-1 / Tubulin alpha-3 chain


Mass: 50188.441 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Respiratory epithelial cells / References: UniProt: Q71U36
#2: Protein Tubulin beta-4B chain / Tubulin beta-2 chain / Tubulin beta-2C chain


Mass: 49877.824 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Cell line: Respiratory epithelial cells / References: UniProt: P68371
#3: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: GTP, energy-carrying molecule*YM
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: TUBB4B and TUBA1A Heterodimer from Human Respiratory Doublet Microtubules
Type: COMPLEX / Entity ID: #1-#2 / Source: NATURAL
Molecular weightValue: 0.0996 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.3
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 64000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: UCSF ChimeraX / Version: 1.5/v9 / Classification: model building / URL: https://www.rbvi.ucsf.edu/chimerax/ / Os: Linux / Type: package
EM software
IDNameCategory
2SerialEMimage acquisition
4CTFFINDCTF correction
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 208558 / Symmetry type: POINT

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