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- EMDB-38989: Cryo-EM structure of full-length MICAL1 in the autoinhibited state -

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Basic information

Entry
Database: EMDB / ID: EMD-38989
TitleCryo-EM structure of full-length MICAL1 in the autoinhibited state
Map data
Sample
  • Complex: full-length MICAL1 protein
    • Protein or peptide: [F-actin]-monooxygenase MICAL1
  • Ligand: ZINC ION
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE
KeywordsMICAL1 / Monooxygenase / F-actin disassembly / autoinhibition / OXIDOREDUCTASE
Function / homology
Function and homology information


hippocampal mossy fiber expansion / : / F-actin monooxygenase / F-actin monooxygenase activity / NAD(P)H oxidase (H2O2-forming) / sulfur oxidation / regulation of regulated secretory pathway / NAD(P)H oxidase H2O2-forming activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen / actin filament depolymerization ...hippocampal mossy fiber expansion / : / F-actin monooxygenase / F-actin monooxygenase activity / NAD(P)H oxidase (H2O2-forming) / sulfur oxidation / regulation of regulated secretory pathway / NAD(P)H oxidase H2O2-forming activity / oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen / actin filament depolymerization / intermediate filament / intercellular bridge / actin filament bundle assembly / cytoskeleton organization / FAD binding / actin filament / monooxygenase activity / small GTPase binding / SH3 domain binding / actin filament binding / actin cytoskeleton / actin binding / Factors involved in megakaryocyte development and platelet production / midbody / endosome membrane / negative regulation of apoptotic process / protein kinase binding / signal transduction / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
bMERB domain / Bivalent Mical/EHBP Rab binding domain / bMERB domain profile. / DUF3585 / : / LIM zinc-binding domain signature. / LIM domain / Zinc-binding domain present in Lin-11, Isl-1, Mec-3. / Zinc finger, LIM-type / LIM domain profile. ...bMERB domain / Bivalent Mical/EHBP Rab binding domain / bMERB domain profile. / DUF3585 / : / LIM zinc-binding domain signature. / LIM domain / Zinc-binding domain present in Lin-11, Isl-1, Mec-3. / Zinc finger, LIM-type / LIM domain profile. / FAD-binding domain / FAD binding domain / Calponin homology domain / Calponin homology (CH) domain / Calponin homology domain / CH domain superfamily / Calponin homology (CH) domain profile. / FAD/NAD(P)-binding domain superfamily
Similarity search - Domain/homology
[F-actin]-monooxygenase MICAL1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.94 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 relief mechanisms for MICAL monooxygenases in F-actin disassembly.
Authors: Leishu Lin / Jiayuan Dong / Shun Xu / Jinman Xiao / Cong Yu / Fengfeng Niu / Zhiyi Wei /
Abstract: MICAL proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICALs catalyze the oxidation ...MICAL proteins represent a unique family of actin regulators crucial for synapse development, membrane trafficking, and cytokinesis. Unlike classical actin regulators, MICALs catalyze the oxidation of specific residues within actin filaments to induce robust filament disassembly. The potent activity of MICALs requires tight control to prevent extensive damage to actin cytoskeleton. However, the molecular mechanism governing MICALs' activity regulation remains elusive. Here, we report the cryo-EM structure of MICAL1 in the autoinhibited state, unveiling a head-to-tail interaction that allosterically blocks enzymatic activity. The structure also reveals the assembly of C-terminal domains via a tripartite interdomain interaction, stabilizing the inhibitory conformation of the RBD. Our structural, biochemical, and cellular analyses elucidate a multi-step mechanism to relieve MICAL1 autoinhibition in response to the dual-binding of two Rab effectors, revealing its intricate activity regulation mechanisms. Furthermore, our mutagenesis study of MICAL3 suggests the conserved autoinhibition and relief mechanisms among MICALs.
History
DepositionFeb 2, 2024-
Header (metadata) releaseAug 28, 2024-
Map releaseAug 28, 2024-
UpdateSep 25, 2024-
Current statusSep 25, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_38989.png

Downloads & links

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Map

FileDownload / File: emd_38989.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 200 pix.
= 215.2 Å		1.08 Å/pix.
x 200 pix.
= 215.2 Å		1.08 Å/pix.
x 200 pix.
= 215.2 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.076 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.0016506077 - 2.1085122
Average (Standard dev.)0.0018344056 (±0.031658344)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 215.2 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_38989_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_38989_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : full-length MICAL1 protein

EntireName: full-length MICAL1 protein
Components
  • Complex: full-length MICAL1 protein
    • Protein or peptide: [F-actin]-monooxygenase MICAL1
  • Ligand: ZINC ION
  • Ligand: FLAVIN-ADENINE DINUCLEOTIDE

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Supramolecule #1: full-length MICAL1 protein

SupramoleculeName: full-length MICAL1 protein / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 106 KDa

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Macromolecule #1: [F-actin]-monooxygenase MICAL1

MacromoleculeName: [F-actin]-monooxygenase MICAL1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: F-actin monooxygenase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 118.014734 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MASPTSTNPA HAHFESFLQA QLCQDVLSSF QELCGALGLE PGGGLPQYHK IKDQLNYWSA KSLWTKLDKR AGQPVYQQGR ACTSTKCLV VGAGPCGLRV AVELALLGAR VVLVEKRTKF SRHNVLHLWP FTIHDLRALG AKKFYGRFCT GTLDHISIRQ L QLLLLKVA ...String:
MASPTSTNPA HAHFESFLQA QLCQDVLSSF QELCGALGLE PGGGLPQYHK IKDQLNYWSA KSLWTKLDKR AGQPVYQQGR ACTSTKCLV VGAGPCGLRV AVELALLGAR VVLVEKRTKF SRHNVLHLWP FTIHDLRALG AKKFYGRFCT GTLDHISIRQ L QLLLLKVA LLLGVEIHWG VTFTGLQPPP RKGSGWRAQL QPNPPAQLAN YEFDVLISAA GGKFVPEGFK VREMRGKLAI GI TANFVNG RTVEETQVPE ISGVARIYNQ SFFQSLLKAT GIDLENIVYY KDDTHYFVMT AKKQCLLRLG VLRQDWPDTN RLL GSANVV PEALQRFTRA AADFATHGKL GKLEFAQDAH GQPDVSAFDF TSMMRAESSA RVQEKHGARL LLGLVGDCLV EPFW PLGTG VARGFLAAFD AAWMVKRWAE GAESLEVLAE RESLYQLLSQ TSPENMHRNV AQYGLDPATR YPNLNLRAVT PNQVR DLYD VLAKEPVQRN NDKTDTGMPA TGSAGTQEEL LRWCQEQTAG YPGVHVSDLS SSWADGLALC ALVYRLQPGL LEPSEL QGL GALEATAWAL KVAENELGIT PVVSAQAVVA GSDPLGLIAY LSHFHSAFKS MAHSPGPVSQ ASPGTSSAVL FLSKLQR TL QRSRAKENAE DAGGKKLRLE MEAETPSTEV PPDPEPGVPL TPPSQHQEAG AGDLCALCGE HLYVLERLCV NGHFFHRS C FRCHTCEATL WPGGYEQHPG DGHFYCLQHL PQTDHKAEGS DRGPESPELP TPSENSMPPG LSTPTASQEG AGPVPDPSQ PTRRQIRLSS PERQRLSSLN LTPDPEMEPP PKPPRSCSAL ARHALESSFV GWGLPVQSPQ ALVAMEKEEK ESPFSSEEEE EDVPLDSDV EQALQTFAKT SGTMNNYPTW RRTLLRRAKE EEMKRFCKAQ TIQRRLNEIE AALRELEAEG VKLELALRRQ S SSPEQQKK LWVGQLLQLV DKKNSLVAEE AELMITVQEL NLEEKQWQLD QELRGYMNRE ENLKTAADRQ AEDQVLRKLV DL VNQRDAL IRFQEERRLS ELALGTGAQG

UniProtKB: [F-actin]-monooxygenase MICAL1

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Macromolecule #2: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 2 / Number of copies: 2 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #3: FLAVIN-ADENINE DINUCLEOTIDE

MacromoleculeName: FLAVIN-ADENINE DINUCLEOTIDE / type: ligand / ID: 3 / Number of copies: 1 / Formula: FAD
Molecular weightTheoretical: 785.55 Da
Chemical component information

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

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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

Concentration0.3 mg/mL
BufferpH: 7.5
Details: 50 mM Tris, pH 7.5, 100 mM NaCl, 2 mM MgCl2, 2 mM DTT.
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / 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: 9063162
Startup modelType of model: INSILICO MODEL
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.94 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.1) / Number images used: 122086
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.1)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 3.1)

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Atomic model buiding 1

Initial model
PDB IDChain

2bry

source_name: PDB, initial_model_type: experimental model

2dk9

source_name: PDB, initial_model_type: experimental model

2co8

source_name: PDB, initial_model_type: experimental model

5le0

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

PDB-8y6k:
Cryo-EM structure of full-length MICAL1 in the autoinhibited state

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