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- EMDB-37260: Cryo-EM structure of Myosin VI in the autoinhibited state (withou... -

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Entry
Database: EMDB / ID: EMD-37260
TitleCryo-EM structure of Myosin VI in the autoinhibited state (without SAH-extension density)
Map datacryo-EM map of autoinhibited MyoVI without SAH-extension
Sample
  • Complex: Complex of Myosin VI and Calmodulin
    • Complex: myosin VI
      • Protein or peptide: Unconventional myosin-VI
    • Complex: Calmodulin
      • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHATE ION
Keywordsmyosin VI / autoinhibition / intracellular transport / MOTOR PROTEIN
Function / homology
Function and homology information


CaMK IV-mediated phosphorylation of CREB / Cam-PDE 1 activation / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Glycogen breakdown (glycogenolysis) / Activation of RAC1 downstream of NMDARs / Reduction of cytosolic Ca++ levels / Sodium/Calcium exchangers / Activation of Ca-permeable Kainate Receptor / CLEC7A (Dectin-1) induces NFAT activation / Synthesis of IP3 and IP4 in the cytosol ...CaMK IV-mediated phosphorylation of CREB / Cam-PDE 1 activation / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Glycogen breakdown (glycogenolysis) / Activation of RAC1 downstream of NMDARs / Reduction of cytosolic Ca++ levels / Sodium/Calcium exchangers / Activation of Ca-permeable Kainate Receptor / CLEC7A (Dectin-1) induces NFAT activation / Synthesis of IP3 and IP4 in the cytosol / RHO GTPases activate PAKs / Calmodulin induced events / Inactivation, recovery and regulation of the phototransduction cascade / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / Calcineurin activates NFAT / eNOS activation / Ion transport by P-type ATPases / Unblocking of NMDA receptors, glutamate binding and activation / regulation of secretion / Protein methylation / RAF activation / VEGFR2 mediated vascular permeability / RAS processing / minus-end directed microfilament motor activity / Ca2+ pathway / presynaptic endocytosis / unconventional myosin complex / FCERI mediated Ca+2 mobilization / Smooth Muscle Contraction / Extra-nuclear estrogen signaling / RHO GTPases activate IQGAPs / RAF/MAP kinase cascade / PKA activation / actin filament-based movement / inner ear auditory receptor cell differentiation / Platelet degranulation / clathrin-coated vesicle membrane / Stimuli-sensing channels / Gap junction degradation / Ion homeostasis / type 3 metabotropic glutamate receptor binding / Trafficking of AMPA receptors / RHOBTB1 GTPase cycle / inner ear morphogenesis / organelle localization by membrane tethering / microfilament motor activity / autophagosome membrane docking / mitochondrion-endoplasmic reticulum membrane tethering / regulation of cardiac muscle cell action potential / nitric-oxide synthase binding / negative regulation of ryanodine-sensitive calcium-release channel activity / filamentous actin / protein phosphatase activator activity / cytoskeletal motor activity / microvillus / RHOU GTPase cycle / adenylate cyclase binding / endocytic vesicle / calyx of Held / DNA damage response, signal transduction by p53 class mediator / catalytic complex / detection of calcium ion / regulation of cardiac muscle contraction / regulation of ryanodine-sensitive calcium-release channel activity / RHOBTB2 GTPase cycle / calcium channel inhibitor activity / cellular response to interferon-beta / phosphatidylinositol 3-kinase binding / voltage-gated potassium channel complex / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / clathrin-coated pit / : / titin binding / sperm midpiece / ruffle / calcium channel complex / nitric-oxide synthase regulator activity / adenylate cyclase activator activity / autophagosome / regulation of heart rate / sarcomere / protein serine/threonine kinase activator activity / regulation of cytokinesis / filopodium / actin filament organization / spindle microtubule / actin filament / intracellular protein transport / positive regulation of receptor signaling pathway via JAK-STAT / sensory perception of sound / ADP binding / cellular response to type II interferon / ruffle membrane / spindle pole / endocytosis / calcium-dependent protein binding / G2/M transition of mitotic cell cycle / actin filament binding / protein localization / actin cytoskeleton
Similarity search - Function
Myosin VI, cargo binding domain / Class VI myosin, motor domain / : / Myosin VI cargo binding domain / Myosin VI, lever arm / Myosin S1 fragment, N-terminal / Myosin, N-terminal, SH3-like / Myosin N-terminal SH3-like domain profile. / Myosin head, motor domain / Myosin head (motor domain) ...Myosin VI, cargo binding domain / Class VI myosin, motor domain / : / Myosin VI cargo binding domain / Myosin VI, lever arm / Myosin S1 fragment, N-terminal / Myosin, N-terminal, SH3-like / Myosin N-terminal SH3-like domain profile. / Myosin head, motor domain / Myosin head (motor domain) / Myosin motor domain profile. / Myosin. Large ATPases. / : / Kinesin motor domain superfamily / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Calmodulin-1 / Unconventional myosin-VI
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.54 Å
AuthorsNiu F / Wei Z
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31971131 China
National Natural Science Foundation of China (NSFC)32170697 China
CitationJournal: Nat Commun / Year: 2024
Title: Autoinhibition and activation of myosin VI revealed by its cryo-EM structure.
Authors: Fengfeng Niu / Lingxuan Li / Lei Wang / Jinman Xiao / Shun Xu / Yong Liu / Leishu Lin / Cong Yu / Zhiyi Wei /
Abstract: Myosin VI is the only molecular motor that moves towards the minus end along actin filaments. Numerous cellular processes require myosin VI and tight regulations of the motor's activity. Defects in ...Myosin VI is the only molecular motor that moves towards the minus end along actin filaments. Numerous cellular processes require myosin VI and tight regulations of the motor's activity. Defects in myosin VI activity are known to cause genetic diseases such as deafness and cardiomyopathy. However, the molecular mechanisms underlying the activity regulation of myosin VI remain elusive. Here, we determined the high-resolution cryo-electron microscopic structure of myosin VI in its autoinhibited state. Our structure reveals that autoinhibited myosin VI adopts a compact, monomeric conformation via extensive interactions between the head and tail domains, orchestrated by an elongated single-α-helix region resembling a "spine". This autoinhibited structure effectively blocks cargo binding sites and represses the motor's ATPase activity. Certain cargo adaptors such as GIPC can release multiple inhibitory interactions and promote motor activity, pointing to a cargo-mediated activation of the processive motor. Moreover, our structural findings allow rationalization of disease-associated mutations in myosin VI. Beyond the activity regulation mechanisms of myosin VI, our study also sheds lights on how activities of other myosin motors such as myosin VII and X might be regulated.
History
DepositionAug 23, 2023-
Header (metadata) releaseFeb 21, 2024-
Map releaseFeb 21, 2024-
UpdateMay 8, 2024-
Current statusMay 8, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37260.png

Downloads & links

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Map

FileDownload / File: emd_37260.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationcryo-EM map of autoinhibited MyoVI without SAH-extension
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 440 pix.
= 363.88 Å		0.83 Å/pix.
x 440 pix.
= 363.88 Å		0.83 Å/pix.
x 440 pix.
= 363.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.827 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0018005248 - 2.1852524
Average (Standard dev.)0.00049588 (±0.01583973)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 363.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half map B

Fileemd_37260_half_map_1.map
Annotationhalf_map_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map A

Fileemd_37260_half_map_2.map
Annotationhalf_map_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Myosin VI and Calmodulin

EntireName: Complex of Myosin VI and Calmodulin
Components
  • Complex: Complex of Myosin VI and Calmodulin
    • Complex: myosin VI
      • Protein or peptide: Unconventional myosin-VI
    • Complex: Calmodulin
      • Protein or peptide: Calmodulin-1
  • Ligand: CALCIUM ION
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHATE ION

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Supramolecule #1: Complex of Myosin VI and Calmodulin

SupramoleculeName: Complex of Myosin VI and Calmodulin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: myosin VI

SupramoleculeName: myosin VI / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Calmodulin

SupramoleculeName: Calmodulin / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Calmodulin-1

MacromoleculeName: Calmodulin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 16.852545 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MADQLTEEQI AEFKEAFSLF DKDGDGTITT KELGTVMRSL GQNPTEAELQ DMINEVDADG NGTIDFPEFL TMMARKMKDT DSEEEIREA FRVFDKDGNG YISAAELRHV MTNLGEKLTD EEVDEMIREA DIDGDGQVNY EEFVQMMTAK

UniProtKB: Calmodulin-1

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Macromolecule #2: Unconventional myosin-VI

MacromoleculeName: Unconventional myosin-VI / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 148.952766 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEDGKPVWAP HPTDGFQMGN IVDIGPDSLT IEPLNQKGKT FLALINQVFP AEEDSKKDVE DNCSLMYLNE ATLLHNIKVR YSKDRIYTY VANILIAVNP YFDIPKIYSS EAIKSYQGKS LGTRPPHVFA IADKAFRDMK VLKMSQSIIV SGESGAGKTE N TKFVLRYL ...String:
MEDGKPVWAP HPTDGFQMGN IVDIGPDSLT IEPLNQKGKT FLALINQVFP AEEDSKKDVE DNCSLMYLNE ATLLHNIKVR YSKDRIYTY VANILIAVNP YFDIPKIYSS EAIKSYQGKS LGTRPPHVFA IADKAFRDMK VLKMSQSIIV SGESGAGKTE N TKFVLRYL TESYGTGQDI DDRIVEANPL LEAFGNAKTV RNNNSSRFGK FVEIHFNEKS SVVGGFVSHY LLEKSRICVQ GK EERNYHI FYRLCAGASE DIREKLHLSS PDNFRYLNRG CTRYFANKET DKQILQNRKS PEYLKAGSMK DPLLDDHGDF IRM CTAMKK IGLDDEEKLD LFRVVAGVLH LGNIDFEEAG STSGGCNLKN KSAQSLEYCA ELLGLDQDDL RVSLTTRVML TTAG GTKGT VIKVPLKVEQ ANNARDALAK TVYSHLFDHV VNRVNQCFPF ETSSYFIGVL DIAGFEYFEH NSFEQFCINY CNEKL QQFF NERILKEEQE LYQKEGLGVN EVHYVDNQDC IDLIEAKLVG ILDILDEENR LPQPSDQHFT SAVHQKHKDH FRLTIP RKS KLAVHRNIRD DEGFIIRHFA GAVCYETTQF VEKNNDALHM SLESLICESR DKFIRELFES STNNNKDTKQ KAGKLSF IS VGNKFKTQLN LLLDKLRSTG ASFIRCIKPN LKMTSHHFEG AQILSQLQCS GMVSVLDLMQ GGYPSRASFH ELYNMYKK Y MPDKLARLDP RLFCKALFKA LGLNENDYKF GLTKVFFRPG KFAEFDQIMK SDPDHLAELV KRVNHWLTCS RWKKVQWCS LSVIKLKNKI KYRAEACIKM QKTIRMWLCK RRHKPRIDGL VKVGTLKKRL DKFNEVVSVL KDGKPEMNKQ IKNLEISIDT LMAKIKSTM MTQEQIQKEY DALVKSSEEL LSALQKKKQQ EEEAERLRRI QEEMEKERKR REEDEKRRRK EEEERRMKLE M EAKRKQEE EERKKREDDE KRIQAEVEAQ LARQKEEESQ QQAVLEQERR DRELALRIAQ SEAELISDEA QADLALRRND GT RPKMTPE QMAKEMSEFL SRGPAVLATK AAAGTKKYDL SKWKYAELRD TINTSCDIEL LAACREEFHR RLKVYHAWKS KNK KRNTET EQRAPKSVTD YDFAPFLNNS PQQNPAAQIP ARQREIEMNR QQRFFRIPFI RPADQYKDPQ SKKKGWWYAH FDGP WIARQ MELHPDKPPI LLVAGKDDME MCELNLEETG LTRKRGAEIL PRQFEEIWER CGGIQYLQNA IESRQARPTY ATAML QSLL K

UniProtKB: Unconventional myosin-VI

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Macromolecule #3: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 3 / Number of copies: 4 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #4: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / 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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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #6: PHOSPHATE ION

MacromoleculeName: PHOSPHATE ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: PO4
Molecular weightTheoretical: 94.971 Da
Chemical component information

ChemComp-PO4:
PHOSPHATE ION

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 2.0 sec. / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 10544925
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

2v26

Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.54 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.0) / Number images used: 173658
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.0)
Final 3D classificationSoftware: (Name: cryoSPARC (ver. 4.0), RELION (ver. 3.1))

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Atomic model buiding 1

Initial model
PDB IDChain

2v26

source_name: PDB, initial_model_type: experimental model

3gn4

source_name: PDB, initial_model_type: experimental model

6obi

source_name: PDB, initial_model_type: experimental model

2n12

source_name: PDB, initial_model_type: experimental model

2kia

source_name: PDB, initial_model_type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8w41:
Cryo-EM structure of Myosin VI in the autoinhibited state

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