Affinage

MICAL3

[F-actin]-monooxygenase MICAL3 · UniProt Q7RTP6

Length
2002 aa
Mass
224.3 kDa
Annotated
2026-06-10
27 papers in source corpus 12 papers cited in narrative 12 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MICAL3 is a flavoprotein monooxygenase that couples NADPH-dependent redox chemistry to direct remodeling of the actin cytoskeleton and to scaffolding of membrane-trafficking machinery (PMID:29343822, PMID:21596566). As an enzyme, it binds F-actin through its calponin-homology (CH) domain, which dramatically stimulates its catalytic efficiency and allows it to oxidize actin methionine residues M44/M47, dismantling filaments and limiting polymerization; this oxidation is reversed by MsrB/SelR reductases (PMID:29343822). A crystal structure of the FMO and CH domains shows an FAD/NADP-binding Rossmann fold, and mutation of Glu213 (FMO) or Arg530 (CH) abolishes the F-actin-stimulated activation, defining the structural basis of substrate-coupled catalysis (PMID:31949908). Independently of its enzymatic activity, MICAL3 acts as a Rab effector and trafficking scaffold: it links Rab8A-positive exocytotic vesicles to ELKS at the cell cortex, where its monooxygenase activity is required for remodeling the docking complex to permit vesicle fusion (PMID:21596566, PMID:22307087). The same scaffolding logic operates during cytokinesis, where MICAL3 binds the centralspindlin component MKLP1, is recruited to the central spindle and midbody, and targets ELKS and Rab8A vesicles there to support abscission (PMID:27528609). Through its actin-regulatory and trafficking functions MICAL3 contributes to broader cellular processes including semaphorin/plexin-directed cytoskeletal reorganization and motor neuron somal positioning (PMID:17971221), symmetric division of cancer stem-like cells via a Semaphorin 3-induced MICAL3/CRMP2/Numb complex (PMID:30587593), cilia-directed cargo delivery (PMID:26485645), and pronuclear envelope breakdown downstream of CHK1 (PMID:39358552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2005 Medium

    Established the first molecular handle on MICAL3 by placing it at the microtubule cytoskeleton as a candidate Rab1-binding protein, raising the question of whether it functions in membrane trafficking.

    Evidence Yeast two-hybrid and GST pulldown for Rab1 binding, immunofluorescence with nocodazole

    PMID:15694364

    Open questions at the time
    • Rab1 interaction not validated by reciprocal endogenous Co-IP
    • no functional consequence of the microtubule association defined
  2. 2007 Medium

    Showed MICAL3 acts as a cytoplasmic effector of semaphorin signaling, answering whether it transduces guidance cues into cytoskeletal control in vivo.

    Evidence RNAi knockdown in chick embryo motor neurons, somal positioning analysis

    PMID:17971221

    Open questions at the time
    • molecular link between Neuropilin-2/Plexin-A2 and MICAL3 not biochemically defined
    • single in vivo system
  3. 2011 High

    Defined MICAL3 as a scaffold bridging Rab8A vesicles and ELKS at the cortex and showed its monooxygenase activity is required for vesicle fusion, establishing a catalytic role in exocytosis.

    Evidence Reciprocal Co-IP, live-cell vesicle imaging, dominant-negative monooxygenase mutant, FRAP

    PMID:21596566

    Open questions at the time
    • redox substrate at the docking site not identified
    • structural geometry of the Rab8A-MICAL3-ELKS bridge unresolved
  4. 2012 Medium

    Distinguished MICAL3 as a bona fide Rab effector and tied its monooxygenase-dependent ROS production to actin stress fiber organization in non-neural cells.

    Evidence Binding assays with phosphocholinated Rabs; siRNA knockdown with ROS inhibitor and actin immunofluorescence

    PMID:22307087 PMID:22331357

    Open questions at the time
    • effector-versus-GEF/GDI selectivity tested only biochemically
    • ROS-dependence inferred from inhibitors rather than direct substrate identification
  5. 2015 Medium

    Extended MICAL3's Rab8-coupled trafficking role to the ciliary base, linking it to NINL-directed cargo delivery.

    Evidence Co-IP interactome, zebrafish morpholino knockdown, immunolocalization

    PMID:26485645

    Open questions at the time
    • direct versus indirect association with NINL not separated
    • enzymatic requirement at cilia not tested
  6. 2016 High

    Resolved that MICAL3's midbody function is structural by showing direct MKLP1 binding and vesicle targeting that supports abscission independently of monooxygenase activity, dissociating scaffolding from catalysis.

    Evidence Cross-linking mass spectrometry, MICAL3 knockout, cytokinesis-failure and abscission-timing assays

    PMID:27528609

    Open questions at the time
    • how MKLP1 recruitment is temporally regulated unknown
    • whether catalytic activity contributes elsewhere in cytokinesis not addressed
  7. 2017 Medium

    Defined the minimal binding interfaces of the MICAL3/ELKS/Rab8A exocytic complex, providing structural constraints on the assembly.

    Evidence Cross-linking mass spectrometry with deletion analysis

    PMID:29044157

    Open questions at the time
    • interfaces mapped by XL-MS, not high-resolution structure
    • stoichiometry of the assembly not determined
  8. 2018 High

    Established the core enzymatic mechanism: MICAL3 directly binds and oxidizes F-actin at methionine M44/M47 to disassemble filaments, a modification reversed by MsrB/SelR reductases, defining a redox switch on actin.

    Evidence In vitro F-actin binding/disassembly and NADPH assays, MS of oxidized residues, Drosophila genetics

    PMID:29343822

    Open questions at the time
    • regulation of catalysis in the cellular context not fully defined
    • relationship between actin oxidation and vesicle-docking remodeling unresolved
  9. 2018 Medium

    Connected MICAL3 monooxygenase activity to cell-fate control by showing a Semaphorin 3-induced MICAL3/CRMP2/Numb complex drives symmetric division of cancer stem-like cells.

    Evidence Co-IP, siRNA knockdown, sphere formation and symmetric/asymmetric division quantification

    PMID:30587593

    Open questions at the time
    • mechanism linking Numb stabilization to MICAL3 catalysis unclear
    • directness of CRMP2/Numb interactions not established
  10. 2020 High

    Provided the structural and kinetic basis for substrate-coupled activation, showing F-actin stimulates catalysis only when the CH domain is present and identifying Glu213 and Arg530 as essential for this allostery.

    Evidence X-ray crystallography of FMO/CH domains, kinetic assays, E213A/R530A mutagenesis

    PMID:31949908

    Open questions at the time
    • full-length enzyme structure including regulatory regions not solved
    • conformational coupling between CH and FMO domains not visualized
  11. 2024 Medium

    Identified CHK1 as an upstream regulator of MICAL3 activity in zygotes, where excessive MICAL3-driven actin depolymerization disrupts pronuclear envelope breakdown.

    Evidence Co-IP/MS from mouse zygotes, gain-of-function CHK1 mutants, F-actin imaging

    PMID:39358552

    Open questions at the time
    • whether CHK1 directly phosphorylates MICAL3 not shown
    • single in vivo system, no reconstitution of the regulatory step

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MICAL3's two activities — actin-oxidizing catalysis and Rab/centralspindlin scaffolding — are spatially and temporally integrated within a single cell remains unresolved.
  • no unified model coupling redox actin remodeling to vesicle docking at exocytic and midbody sites
  • upstream signals selecting between catalytic and scaffolding modes not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005856 cytoskeleton 2 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-1640170 Cell Cycle 1
Complex memberships
MICAL3/CRMP2/Numb complexMICAL3/ELKS/Rab8A exocytic complex

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 MICAL3 interacts with both Rab8A and ELKS, linking these two proteins. Rab8A associates with exocytotic vesicles in a Rab6-dependent manner, and MICAL3 acts as a scaffold connecting Rab8A and ELKS at the cell cortex. Expression of a MICAL3 mutant with an inactive monooxygenase domain caused strong accumulation of secretory vesicles docked at the cell cortex that failed to fuse with the plasma membrane, indicating that MICAL3's monooxygenase activity is required for vesicle-docking complex remodeling and fusion. Co-immunoprecipitation, live-cell imaging of vesicle dynamics, dominant-negative monooxygenase mutant expression, FRAP Current biology : CB High 21596566
2005 MICAL3 interacts with Rab1 in yeast two-hybrid and GST pulldown experiments. MICAL3 localizes to a microtubule-associated compartment, as treatment with the microtubule-depolymerizing drug nocodazole disrupts this localization, indicating a link between MICAL3 and the microtubule cytoskeleton. Yeast two-hybrid, GST pulldown, immunofluorescence with nocodazole treatment Biochemical and biophysical research communications Medium 15694364
2007 Knockdown of MICAL3 in chick motor neurons via RNAi caused ectopic positioning of motor neuron cell bodies in the peripheral nervous system, placing MICAL3 downstream of Neuropilin-2/Plexin-A2 semaphorin signaling as a cytoplasmic effector that controls somal positioning through cytoskeletal reorganization. RNA interference in chick embryo, analysis of motor neuron positioning Neural development Medium 17971221
2012 MICAL3 (as MICAL-3) was shown to interact with Rab1 and Rab35 effector binding is only slightly inhibited by phosphocholination, in contrast to GEF and GDI interactions which are strongly inhibited, demonstrating that MICAL-3 functions as a Rab effector protein. Biochemical binding assays with phosphocholinated Rab proteins, quantitative interaction measurements The EMBO journal Medium 22307087
2012 Human MICAL3, like MICAL1 and MICAL2, is required for normal actin stress fiber organization in non-neural cells, and this actin-regulatory function depends on its generation of reactive oxygen species (ROS) via the monooxygenase domain. siRNA knockdown, ROS inhibitor treatment, immunofluorescence of actin stress fibers Journal of cell science Medium 22331357
2015 MICAL3 was identified as part of a NINL-associated interactome at the base of cilia, and interacts with Rab8 to regulate vesicle docking and fusion for cilia-directed cargo delivery. Genetic interaction between NINL and CC2D2A was demonstrated in zebrafish, and MICAL3 was linked to this pathway. Co-immunoprecipitation/interactome analysis, zebrafish morpholino knockdown, immunolocalization PLoS genetics Medium 26485645
2016 MICAL3 forms a direct complex with the centralspindlin component MKLP1, is recruited to the central spindle and midbody during cytokinesis, and targets ELKS and Rab8A-positive vesicles to the midbody. Knockout of MICAL3 increases cytokinetic failure frequency and delays abscission. This scaffolding function is independent of MICAL3's enzymatic monooxygenase activity. Cross-linking mass spectrometry, MICAL3 knockout, cell biological assays (cytokinesis failure quantification, abscission timing), immunofluorescence The Journal of biological chemistry High 27528609
2017 Cross-linking mass spectrometry combined with deletion analysis defined the minimal binding domains of the MICAL3/ELKS/Rab8A complex involved in exocytosis, providing structural constraints on this protein assembly. Cross-linking mass spectrometry (XL-MS), deletion analysis, biochemical interaction assays Scientific reports Medium 29044157
2018 Human MICAL3 directly associates with F-actin, which activates its catalytic activity. MICAL3 uses NADPH-dependent redox activity to oxidize actin methionine residues M44/M47, dismantling filaments and limiting polymerization. MsrB/SelR reductase enzymes counteract MICAL3's effect on F-actin both in vitro and in vivo. In vitro F-actin binding and disassembly assays, NADPH consumption assays, genetic experiments in Drosophila, mass spectrometry of oxidized actin residues Scientific reports High 29343822
2018 Semaphorin 3 stimulation induces interaction among MICAL3, CRMP2, and Numb in breast cancer stem-like cells. MICAL3 monooxygenase activity (MO activity) is required for this interaction, for Numb protein accumulation, and for symmetric cell division. MICAL3 knockdown decreases sphere formation and shifts CSCs from symmetric to asymmetric division. Co-immunoprecipitation, MICAL3 siRNA knockdown, sphere formation assay, division mode quantification (symmetric vs. asymmetric) Proceedings of the National Academy of Sciences of the United States of America Medium 30587593
2020 Crystal structure of human MICAL3 FMO and calponin-homology (CH) domains was solved. MICAL3 contains an FAD/NADP-binding Rossmann-fold domain for monooxygenase activity. Kinetic analysis showed that F-actin dramatically increases MICAL3 catalytic efficiency only when the CH domain is present. Mutation of Glu213 in the FMO domain and Arg530 in the CH domain abolished this F-actin-stimulated catalytic activation. X-ray crystallography, kinetic enzyme assays, site-directed mutagenesis (E213A, R530A) IUCrJ High 31949908
2024 CHK1 physically interacts with MICAL3 in mouse zygotes, as identified by co-immunoprecipitation and mass spectrometry. Gain-of-function CHK1 mutants enhance interaction with MICAL3 and increase MICAL3 enzymatic activity, causing excessive F-actin depolymerization that disrupts pronuclear envelope breakdown. Co-immunoprecipitation and mass spectrometry of ~6000 mouse zygotes, gain-of-function CHK1 mutant analysis, F-actin imaging EMBO reports Medium 39358552

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature genetics 456 22001757
1998 Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 190 10048485
2011 Rab6, Rab8, and MICAL3 cooperate in controlling docking and fusion of exocytotic carriers. Current biology : CB 163 21596566
2007 Boundary cap cells constrain spinal motor neuron somal migration at motor exit points by a semaphorin-plexin mechanism. Neural development 102 17971221
2012 Reversible phosphocholination of Rab proteins by Legionella pneumophila effector proteins. The EMBO journal 91 22307087
2012 Differential regulation of actin microfilaments by human MICAL proteins. Journal of cell science 85 22331357
2015 The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking. PLoS genetics 71 26485645
2017 Emerging roles of MICAL family proteins - from actin oxidation to membrane trafficking during cytokinesis. Journal of cell science 69 28373242
2005 The MICAL proteins and rab1: a possible link to the cytoskeleton? Biochemical and biophysical research communications 58 15694364
2009 Muscle genome-wide expression profiling during disease evolution in mdx mice. Physiological genomics 54 19223608
2018 Semaphorin signaling via MICAL3 induces symmetric cell division to expand breast cancer stem-like cells. Proceedings of the National Academy of Sciences of the United States of America 49 30587593
2018 The MICALs are a Family of F-actin Dismantling Oxidoreductases Conserved from Drosophila to Humans. Scientific reports 40 29343822
2023 MICAL-mediated oxidation of actin and its effects on cytoskeletal and cellular dynamics. Frontiers in cell and developmental biology 28 36875759
2016 MICAL3 Flavoprotein Monooxygenase Forms a Complex with Centralspindlin and Regulates Cytokinesis. The Journal of biological chemistry 24 27528609
2017 Facilitating identification of minimal protein binding domains by cross-linking mass spectrometry. Scientific reports 18 29044157
2021 Down-regulation of a panel of immune-related lncRNAs in breast cancer. Pathology, research and practice 14 34175685
2023 Disassembly of bundled F-actin and cellular remodeling via an interplay of Mical, cofilin, and F-actin crosslinkers. Proceedings of the National Academy of Sciences of the United States of America 13 37725655
2014 MicroRNA 648 Targets ET-1 mRNA and is cotranscriptionally regulated with MICAL3 by PAX5. Molecular and cellular biology 13 25403488
2020 Structural and kinetic insights into flavin-containing monooxygenase and calponin-homology domains in human MICAL3. IUCrJ 12 31949908
2012 Allelic expression analysis of the osteoarthritis susceptibility locus that maps to MICAL3. BMC medical genetics 6 22385522
2022 Blood Transcriptome Analysis of Beef Cow with Different Parity Revealed Candidate Genes and Gene Networks Regulating the Postpartum Diseases. Genes 5 36140838
2021 Enhanced Production of the Mical Redox Domain for Enzymology and F-actin Disassembly Assays. International journal of molecular sciences 3 33671465
2024 CHK1 controls zygote pronuclear envelope breakdown by regulating F-actin through interacting with MICAL3. EMBO reports 2 39358552
2024 Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies. bioRxiv : the preprint server for biology 1 38496508
2021 ORN: Inferring patient-specific dysregulation status of pathway modules in cancer with OR-gate Network. PLoS computational biology 1 33819263
2026 Mechanisms of heat and hypoxia defense in the sea cucumber Apostichopus japonicus: Insights from ubiquitination regulation. Comparative biochemistry and physiology. Part D, Genomics & proteomics 0 41795302
2025 The Role of HbA1c in Parkinson's Disease: An Integrative Analysis by Single-Cell, Bulk Transcriptome and Mendelian Randomization. Molecular neurobiology 0 40397357

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