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- PDB-8fh3: Human IFT-A complex structures provide molecular insights into ci... -

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Basic information

Entry
Database: PDB / ID: 8fh3
TitleHuman IFT-A complex structures provide molecular insights into ciliary transport
Components
  • (Intraflagellar transport protein ...) x 2
  • (WD repeat-containing protein ...) x 2
  • Tubby-related protein 3
KeywordsTRANSPORT PROTEIN / IFT-A complex / TULP3 / cilia
Function / homology
Function and homology information


negative regulation of smoothened signaling pathway involved in ventral spinal cord patterning / intraciliary transport particle A binding / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / myotome development / negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning / : / ear morphogenesis / intraciliary transport particle A / intraciliary anterograde transport / ganglion development ...negative regulation of smoothened signaling pathway involved in ventral spinal cord patterning / intraciliary transport particle A binding / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / myotome development / negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning / : / ear morphogenesis / intraciliary transport particle A / intraciliary anterograde transport / ganglion development / cone photoreceptor outer segment / bronchus morphogenesis / digestive system development / embryonic heart tube left/right pattern formation / embryonic body morphogenesis / embryonic neurocranium morphogenesis / photoreceptor cell outer segment organization / 9+0 non-motile cilium / central nervous system neuron differentiation / neural tube patterning / intraciliary retrograde transport / protein localization to ciliary membrane / embryonic camera-type eye development / intraciliary transport / establishment of protein localization to organelle / gonad development / regulation of cilium assembly / spinal cord dorsal/ventral patterning / photoreceptor connecting cilium / ciliary tip / Intraflagellar transport / camera-type eye morphogenesis / embryonic brain development / regulation of G protein-coupled receptor signaling pathway / protein localization to cilium / non-motile cilium assembly / non-motile cilium / embryonic heart tube development / regulation of smoothened signaling pathway / embryonic cranial skeleton morphogenesis / nervous system process / motile cilium / embryonic forelimb morphogenesis / determination of left/right symmetry / embryonic limb morphogenesis / limb development / anterior/posterior pattern specification / ciliary base / embryonic digit morphogenesis / receptor clustering / axoneme / cilium assembly / photoreceptor outer segment / Hedgehog 'off' state / negative regulation of smoothened signaling pathway / phosphatidylinositol-4,5-bisphosphate binding / centriole / cellular response to leukemia inhibitory factor / phosphatidylinositol binding / ciliary basal body / G protein-coupled receptor binding / neural tube closure / brain development / bone development / cell morphogenesis / cilium / heart development / protein-containing complex assembly / in utero embryonic development / cytoskeleton / G protein-coupled receptor signaling pathway / centrosome / protein-containing complex binding / nucleolus / regulation of DNA-templated transcription / enzyme binding / extracellular region / nucleoplasm / membrane / nucleus / plasma membrane / cytoplasm
Similarity search - Function
Tubby, N-terminal / Tubby N-terminal / Tubby, C-terminal / Tubby, C-terminal, conserved site / Tub family / Tub family signature 1. / Tub family signature 2. / Tubby-like, C-terminal / WD repeat protein 35 / WDR19, WD40 repeat ...Tubby, N-terminal / Tubby N-terminal / Tubby, C-terminal / Tubby, C-terminal, conserved site / Tub family / Tub family signature 1. / Tub family signature 2. / Tubby-like, C-terminal / WD repeat protein 35 / WDR19, WD40 repeat / WD repeat-containing protein 19/dyf-2 / WD domain, G-beta repeat / Intraflagellar transport protein 122 homolog / Anaphase-promoting complex subunit 4, WD40 domain / Anaphase-promoting complex subunit 4 WD40 domain / Tetratricopeptide-like helical domain superfamily / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
Tubby-related protein 3 / WD repeat-containing protein 19 / Intraflagellar transport protein 140 homolog / Intraflagellar transport protein 122 homolog / WD repeat-containing protein 35
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.3 Å
AuthorsJiang, M. / Palicharla, V.R. / Miller, D. / Hwang, S.H. / Zhu, H. / Hixson, P. / Mukhopadhyay, S. / Sun, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R00HL143037 United States
CitationJournal: Cell Res / Year: 2023
Title: Human IFT-A complex structures provide molecular insights into ciliary transport.
Authors: Meiqin Jiang / Vivek Reddy Palicharla / Darcie Miller / Sun-Hee Hwang / Hanwen Zhu / Patricia Hixson / Saikat Mukhopadhyay / Ji Sun /
Abstract: Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT ...Intraflagellar transport (IFT) complexes, IFT-A and IFT-B, form bidirectional trains that move along the axonemal microtubules and are essential for assembling and maintaining cilia. Mutations in IFT subunits lead to numerous ciliopathies involving multiple tissues. However, how IFT complexes assemble and mediate cargo transport lacks mechanistic understanding due to missing high-resolution structural information of the holo-complexes. Here we report cryo-EM structures of human IFT-A complexes in the presence and absence of TULP3 at overall resolutions of 3.0-3.9 Å. IFT-A adopts a "lariat" shape with interconnected core and peripheral subunits linked by structurally vital zinc-binding domains. TULP3, the cargo adapter, interacts with IFT-A through its N-terminal region, and interface mutations disrupt cargo transport. We also determine the molecular impacts of disease mutations on complex formation and ciliary transport. Our work reveals IFT-A architecture, sheds light on ciliary transport and IFT train formation, and enables the rationalization of disease mutations in ciliopathies.
History
DepositionDec 13, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 22, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: WD repeat-containing protein 35
B: Intraflagellar transport protein 122 homolog
C: WD repeat-containing protein 19
E: Intraflagellar transport protein 140 homolog
I: Tubby-related protein 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)642,8369
Polymers642,5745
Non-polymers2624
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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WD repeat-containing protein ... , 2 types, 2 molecules AC

#1: Protein WD repeat-containing protein 35 / Intraflagellar transport protein 121 homolog


Mass: 133705.641 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR35, IFT121, KIAA1336 / Production host: Homo sapiens (human) / References: UniProt: Q9P2L0
#3: Protein WD repeat-containing protein 19 / Intraflagellar transport 144 homolog


Mass: 151760.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: WDR19, IFT144, KIAA1638 / Production host: Homo sapiens (human) / References: UniProt: Q8NEZ3

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Intraflagellar transport protein ... , 2 types, 2 molecules BE

#2: Protein Intraflagellar transport protein 122 homolog / / WD repeat-containing protein 10 / WD repeat-containing protein 140


Mass: 141993.703 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IFT122, SPG, WDR10, WDR140 / Production host: Homo sapiens (human) / References: UniProt: Q9HBG6
#4: Protein Intraflagellar transport protein 140 homolog / / WD and tetratricopeptide repeats protein 2


Mass: 165404.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IFT140, KIAA0590, WDTC2 / Production host: Homo sapiens (human) / References: UniProt: Q96RY7

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Protein / Non-polymers , 2 types, 5 molecules I

#5: Protein Tubby-related protein 3 / Tubby-like protein 3


Mass: 49710.059 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TULP3, TUBL3 / Production host: Homo sapiens (human) / References: UniProt: O75386
#6: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn

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Details

Has ligand of interestN

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Experimental details

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Experiment

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

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Intraflagellar transport complex A (IFT-A)COMPLEX#1-#50RECOMBINANT
2IFT-A_TULP3COMPLEX1RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
Buffer solutionpH: 8
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: OTHER
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 53.06 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 4.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 113784 / Symmetry type: POINT

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