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Yorodumi- PDB-8uto: KIF1A[1-393] AMP-PNP bound two-heads-bound state in complex with ... -
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-Basic information
Entry | Database: PDB / ID: 8uto | |||||||||||||||||||||
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Title | KIF1A[1-393] AMP-PNP bound two-heads-bound state in complex with a microtubule - class T2L1 | |||||||||||||||||||||
Components |
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Keywords | MOTOR PROTEIN / KIF1A / kinesin / motility / microtubule / tubulin | |||||||||||||||||||||
Function / homology | Function and homology information neuronal dense core vesicle membrane / dense core granule cytoskeletal transport / anterograde neuronal dense core vesicle transport / retrograde neuronal dense core vesicle transport / regulation of dendritic spine development / cytoskeleton-dependent intracellular transport / regulation of dendritic spine morphogenesis / anterograde axonal transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state ...neuronal dense core vesicle membrane / dense core granule cytoskeletal transport / anterograde neuronal dense core vesicle transport / retrograde neuronal dense core vesicle transport / regulation of dendritic spine development / cytoskeleton-dependent intracellular transport / regulation of dendritic spine morphogenesis / anterograde axonal transport / Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane / Hedgehog 'off' state / Cilium Assembly / Intraflagellar transport / COPI-dependent Golgi-to-ER retrograde traffic / Carboxyterminal post-translational modifications of tubulin / RHOH GTPase cycle / Sealing of the nuclear envelope (NE) by ESCRT-III / Kinesins / PKR-mediated signaling / The role of GTSE1 in G2/M progression after G2 checkpoint / Aggrephagy / Resolution of Sister Chromatid Cohesion / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Separation of Sister Chromatids / Kinesins / plus-end-directed microtubule motor activity / RHO GTPases activate IQGAPs / RHO GTPases Activate Formins / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / COPI-mediated anterograde transport / COPI-dependent Golgi-to-ER retrograde traffic / kinesin complex / microtubule-based movement / neuronal dense core vesicle / cytoskeletal motor activity / vesicle-mediated transport / axon cytoplasm / structural constituent of cytoskeleton / microtubule cytoskeleton organization / microtubule cytoskeleton / mitotic cell cycle / microtubule binding / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule / axon / GTPase activity / dendrite / synapse / GTP binding / perinuclear region of cytoplasm / ATP hydrolysis activity / ATP binding / identical protein binding / metal ion binding / cytoplasm Similarity search - Function | |||||||||||||||||||||
Biological species | Homo sapiens (human) Sus scrofa (pig) | |||||||||||||||||||||
Method | ELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||||||||||||||
Authors | Benoit, M.P.M.H. / Rao, L. / Asenjo, A.B. / Gennerich, A. / Sosa, H. | |||||||||||||||||||||
Funding support | United States, 6items
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Citation | Journal: Nat Commun / Year: 2024 Title: Cryo-EM unveils kinesin KIF1A's processivity mechanism and the impact of its pathogenic variant P305L. Authors: Matthieu P M H Benoit / Lu Rao / Ana B Asenjo / Arne Gennerich / Hernando Sosa / Abstract: Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular ...Mutations in the microtubule-associated motor protein KIF1A lead to severe neurological conditions known as KIF1A-associated neurological disorders (KAND). Despite insights into its molecular mechanism, high-resolution structures of KIF1A-microtubule complexes remain undefined. Here, we present 2.7-3.5 Å resolution structures of dimeric microtubule-bound KIF1A, including the pathogenic P305L mutant, across various nucleotide states. Our structures reveal that KIF1A binds microtubules in one- and two-heads-bound configurations, with both heads exhibiting distinct conformations with tight inter-head connection. Notably, KIF1A's class-specific loop 12 (K-loop) forms electrostatic interactions with the C-terminal tails of both α- and β-tubulin. The P305L mutation does not disrupt these interactions but alters loop-12's conformation, impairing strong microtubule-binding. Structure-function analysis reveals the K-loop and head-head coordination as major determinants of KIF1A's superprocessive motility. Our findings advance the understanding of KIF1A's molecular mechanism and provide a basis for developing structure-guided therapeutics against KAND. | |||||||||||||||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8uto.cif.gz | 591.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8uto.ent.gz | 478.3 KB | Display | PDB format |
PDBx/mmJSON format | 8uto.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8uto_validation.pdf.gz | 2.3 MB | Display | wwPDB validaton report |
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Full document | 8uto_full_validation.pdf.gz | 2.2 MB | Display | |
Data in XML | 8uto_validation.xml.gz | 94.2 KB | Display | |
Data in CIF | 8uto_validation.cif.gz | 139.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ut/8uto ftp://data.pdbj.org/pub/pdb/validation_reports/ut/8uto | HTTPS FTP |
-Related structure data
Related structure data | 42544MC 8utnC 8utpC 8utqC 8utrC 8utsC 8uttC 8utuC 8utvC 8utwC 8utyC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 3 types, 7 molecules KNAESBI
#1: Protein | Mass: 49288.438 Da / Num. of mol.: 2 / Fragment: residues 1-393 Source method: isolated from a genetically manipulated source Details: "linker" residues are comprised of a leucine zipper based on S. cerevisiae GCN4, which is followed by the C-terminal strep-tag Source: (gene. exp.) Homo sapiens (human) / Gene: KIF1A, ATSV, C2orf20 / Production host: Escherichia coli (E. coli) / References: UniProt: Q12756 #2: Protein | Mass: 50204.445 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: Q2XVP4 #3: Protein | Mass: 49999.887 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Sus scrofa (pig) / References: UniProt: A0A287AGU7 |
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-Non-polymers , 5 types, 13 molecules
#4: Chemical | ChemComp-MG / #5: Chemical | #6: Chemical | #7: Chemical | #8: Chemical | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: FILAMENT / 3D reconstruction method: helical reconstruction |
-Sample preparation
Component |
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: Escherichia coli (E. coli) | ||||||||||||||||||||||||
Buffer solution | pH: 6.8 | ||||||||||||||||||||||||
Buffer component |
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Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: UltrAuFoil | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm |
Image recording | Electron dose: 50.22 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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Helical symmerty | Angular rotation/subunit: 168.09 ° / Axial rise/subunit: 5.6 Å / Axial symmetry: C1 |
3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 99325 Details: NUMBER OF ASYMMETRIC UNITS USED IS REPORTED IN "NUMBER OF SEGMENTS USED", DUE TO THE LOCAL PROCESSING STRATEGY EMPLOYED. Symmetry type: HELICAL |
Refinement | Highest resolution: 3.2 Å |