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- EMDB-42551: KIF1A[1-393] P305L mutant ADP bound in complex with a microtubule -

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Entry
Database: EMDB / ID: EMD-42551
TitleKIF1A[1-393] P305L mutant ADP bound in complex with a microtubule
Map dataPrimary map, locally refined on the central asymmetric unit
Sample
  • Complex: KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule
    • Protein or peptide: Tubulin alpha-1B chain
    • Protein or peptide: Tubulin beta-2B chain
    • Protein or peptide: Kinesin-like protein KIF1A
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: TAXOL
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsKIF1A / kinesin / motility / microtubule / tubulin / MOTOR PROTEIN
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 / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / microtubule binding / 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
: / : / Kinesin-like KIF1-type / Kinesin protein 1B / Kinesin-like / Kinesin protein / Kinesin-associated / Kinesin-associated / Forkhead associated domain / Forkhead-associated (FHA) domain profile. ...: / : / Kinesin-like KIF1-type / Kinesin protein 1B / Kinesin-like / Kinesin protein / Kinesin-associated / Kinesin-associated / Forkhead associated domain / Forkhead-associated (FHA) domain profile. / FHA domain / Forkhead-associated (FHA) domain / Kinesin motor domain signature. / Kinesin motor domain, conserved site / Kinesin motor domain / Kinesin motor domain profile. / Kinesin motor, catalytic domain. ATPase. / Kinesin motor domain / SMAD/FHA domain superfamily / Kinesin motor domain superfamily / PH domain / Alpha tubulin / Tubulin-beta mRNA autoregulation signal. / 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 / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / PH-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Tubulin beta chain / Kinesin-like protein KIF1A / Tubulin alpha-1B chain
Similarity search - Component
Biological speciesSus scrofa (pig) / Homo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsBenoit MPMH / Rao L / Asenjo AB / Gennerich A / Sosa H
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM113164 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM098469 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01NS114636 United States
Simons FoundationSF349247 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM103310 United States
CitationJournal: 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
DepositionOct 31, 2023-
Header (metadata) releaseJun 12, 2024-
Map releaseJun 12, 2024-
UpdateJul 31, 2024-
Current statusJul 31, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_42551.png

Downloads & links

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Map

FileDownload / File: emd_42551.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary map, locally refined on the central asymmetric unit
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 416 pix.
= 364.416 Å		0.88 Å/pix.
x 416 pix.
= 364.416 Å		0.88 Å/pix.
x 416 pix.
= 364.416 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.876 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.00453
Minimum - Maximum0.0 - 0.05778295
Average (Standard dev.)0.000359346 (±0.0018812929)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions416416416
Spacing416416416
CellA=B=C: 364.416 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_42551_msk_1.map
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Mask #2

Fileemd_42551_msk_2.map
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Mask #3

Fileemd_42551_msk_3.map
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Mask #4

Fileemd_42551_msk_4.map
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Additional map: Map low pass filtered to 6 A

Fileemd_42551_additional_1.map
AnnotationMap low pass filtered to 6 A
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Additional map: Map low pass filtered to 8 A

Fileemd_42551_additional_2.map
AnnotationMap low pass filtered to 8 A
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Half map: Half map from the gold Standard refinement

Fileemd_42551_half_map_1.map
AnnotationHalf map from the gold Standard refinement
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Half map: Half map from the gold Standard refinement

Fileemd_42551_half_map_2.map
AnnotationHalf map from the gold Standard refinement
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Sample components

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Entire : KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule

EntireName: KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule
Components
  • Complex: KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule
    • Protein or peptide: Tubulin alpha-1B chain
    • Protein or peptide: Tubulin beta-2B chain
    • Protein or peptide: Kinesin-like protein KIF1A
  • Ligand: GUANOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: TAXOL
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule

SupramoleculeName: KIF1A[1-393] P305L mutant ADP in complex with a 15R microtubule
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Macromolecule #1: Tubulin alpha-1B chain

MacromoleculeName: Tubulin alpha-1B chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 50.204445 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 RLISQIVSSI TA SLRFDGA LNVDLTEFQT NLVPYPRIHF PLATYAPVIS AEKAYHEQLS VAEITNACFE PANQMVKCDP RHGKYMACCL LYR GDVVPK DVNAAIATIK TKRSIQFVDW CPTGFKVGIN YQPPTVVPGG DLAKVQRAVC MLSNTTAIAE AWARLDHKFD LMYA KRAFV HWYVGEGMEE GEFSEAREDM AALEKDYEEV GVDSVEGEGE EEGEEY

UniProtKB: Tubulin alpha-1B chain

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Macromolecule #2: Tubulin beta-2B chain

MacromoleculeName: Tubulin beta-2B chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Sus scrofa (pig)
Molecular weightTheoretical: 49.999887 KDa
SequenceString: MREIVHIQAG QCGNQIGAKF WEVISDEHGI DPTGSYHGDS DLQLERINVY YNEATGNKYV PRAILVDLEP GTMDSVRSGP FGQIFRPDN FVFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKESESCDC LQGFQLTHSL GGGTGSGMGT LLISKIREEY P DRIMNTFS ...String:
MREIVHIQAG QCGNQIGAKF WEVISDEHGI DPTGSYHGDS DLQLERINVY YNEATGNKYV PRAILVDLEP GTMDSVRSGP FGQIFRPDN FVFGQSGAGN NWAKGHYTEG AELVDSVLDV VRKESESCDC LQGFQLTHSL GGGTGSGMGT LLISKIREEY P DRIMNTFS VMPSPKVSDT VVEPYNATLS VHQLVENTDE TYCIDNEALY DICFRTLKLT TPTYGDLNHL VSATMSGVTT CL RFPGQLN ADLRKLAVNM VPFPRLHFFM PGFAPLTSRG SQQYRALTVP ELTQQMFDSK NMMAACDPRH GRYLTVAAIF RGR MSMKEV DEQMLNVQNK NSSYFVEWIP NNVKTAVCDI PPRGLKMSAT FIGNSTAIQE LFKRISEQFT AMFRRKAFLH WYTG EGMDE MEFTEAESNM NDLVSEYQQY QDATADEQGE FEEEEGEDEA

UniProtKB: Tubulin beta chain

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Macromolecule #3: Kinesin-like protein KIF1A

MacromoleculeName: Kinesin-like protein KIF1A / type: protein_or_peptide / ID: 3
Details: leucine zipper from S. cerevisiae GCN4 at C-terminus
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.30448 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MAGASVKVAV RVRPFNSREM SRDSKCIIQM SGSTTTIVNP KQPKETPKSF SFDYSYWSHT SPEDINYASQ KQVYRDIGEE MLQHAFEGY NVCIFAYGQT GAGKSYTMMG KQEKDQQGII PQLCEDLFSR INDTTNDNMS YSVEVSYMEI YCERVRDLLN P KNKGNLRV ...String:
MAGASVKVAV RVRPFNSREM SRDSKCIIQM SGSTTTIVNP KQPKETPKSF SFDYSYWSHT SPEDINYASQ KQVYRDIGEE MLQHAFEGY NVCIFAYGQT GAGKSYTMMG KQEKDQQGII PQLCEDLFSR INDTTNDNMS YSVEVSYMEI YCERVRDLLN P KNKGNLRV REHPLLGPYV EDLSKLAVTS YNDIQDLMDS GNKARTVAAT NMNETSSRSH AVFNIIFTQK RHDAETNITT EK VSKISLV DLAGSERADS TGAKGTRLKE GANINKSLTT LGKVISALAE MDSGPNKNKK KKKTDFILYR DSVLTWLLRE NLG GNSRTA MVAALSPADI NYDETLSTLR YADRAKQIRC NAVINEDPNN KLIRELKDEV TRLRDLLYAQ GLGDITDGAG VKQL EDKVE ELASKNYHLE NEVARLKKLV EFTSAWSHPQ FEK

UniProtKB: Kinesin-like protein KIF1A

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Macromolecule #4: GUANOSINE-5'-TRIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / 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 #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #6: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 6 / 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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Macromolecule #7: TAXOL

MacromoleculeName: TAXOL / type: ligand / ID: 7 / Number of copies: 1 / Formula: TA1
Molecular weightTheoretical: 853.906 Da
Chemical component information

ChemComp-TA1:
TAXOL / medication, chemotherapy*YM

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Macromolecule #8: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 8 / Number of copies: 1 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 6.8
Component:
ConcentrationName
80.0 mMK-PIPES
20.0 uMPaclitaxel
5.0 mMMagnesium chloride
1.0 mMEGTA
4.0 mMADP
GridModel: UltrAuFoil / Support film - Material: GOLD
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 62.9 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

Final reconstructionApplied symmetry - Helical parameters - Δz: 5.45 Å
Applied symmetry - Helical parameters - Δ&Phi: 168.09 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF
Details: Number of asymmetric units used is reported in "number of segments used", due to the local processing strategy employed.
Number images used: 119590
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6wwl

Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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