Affinage

CAPZA2

F-actin-capping protein subunit alpha-2 · UniProt P47755

Round 2 corrected
Length
286 aa
Mass
32.9 kDa
Annotated
2026-04-28
82 papers in source corpus 41 papers cited in narrative 42 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CAPZA2 encodes the α2 subunit of the heterodimeric actin-capping protein CapZ, which binds actin filament barbed ends with sub-nanomolar affinity to block both polymerization and depolymerization, thereby controlling filament length and cytoskeletal mechanics (PMID:2557904, PMID:9915586). CapZ activity is regulated by PIP2 binding, PKCε-mediated phosphorylation, and HDAC3-dependent acetylation of the β-subunit C-terminal tentacle, coupling mechanical and hypertrophic signals to thin-filament dynamics in cardiomyocytes (PMID:1653607, PMID:30808692, PMID:27185186). In striated muscle, CapZ anchors thin filament barbed ends at the Z-disc through interactions with nebulin and α-actinin and serves as a scaffold for PKC-βII and PP1α signaling at myofilaments (PMID:18272787, PMID:16870209, PMID:18364747); beyond muscle, CapZ participates in autophagosomal membrane shaping via PtdIns(3)P-stimulated actin assembly and controls early-to-late endosome transition (PMID:26237647, PMID:38273307). Heterozygous damaging de novo mutations in CAPZA2 cause a neurodevelopmental disorder characterized by motor and cognitive delay, seizures, and synaptic structural defects in both humans and mouse models (PMID:32338762, PMID:40659881).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1989 High

    Establishing the core biochemical activity of CapZ resolved how barbed-end capping and nucleation function: CapZ caps barbed ends with ~1 nM affinity, blocks both assembly and disassembly, and nucleates polymerization proportional to its concentration, without severing filaments.

    Evidence Multiple in vitro actin polymerization assays (pyrene-actin, critical concentration, dilution, ultracentrifugation) with purified muscle CapZ

    PMID:2557904

    Open questions at the time
    • No structure available to explain the capping mechanism
    • No information on regulation of capping activity in cells
  2. 1991 High

    Identification of PIP2 as a CapZ inhibitor and of two distinct alpha isoforms established both a regulatory paradigm (phosphoinositide control of capping) and tissue-specific functional diversification of the heterodimer.

    Evidence Pyrene-actin polymerization/viscometry with phospholipid micelles; cDNA cloning and Northern/Southern blotting in chicken tissues

    PMID:1653607 PMID:1661732 PMID:1711931

    Open questions at the time
    • Physiological relevance of PIP2 regulation in intact cells not yet shown
    • No structural basis for how PIP2 uncaps filaments
  3. 1993 High

    Localization of CapZ at nascent Z-discs before actin achieves a striated pattern, combined with loss-of-function showing disrupted sarcomere organization, established CapZ as an early organizer of thin filament polarity during myofibrillogenesis.

    Evidence Double immunofluorescence microscopy during myotube differentiation; anti-CapZ antibody microinjection and dominant-negative mutant expression in skeletal myotubes

    PMID:7822423 PMID:8402953

    Open questions at the time
    • Mechanism of CapZ recruitment to Z-discs before actin independent of binding partners unknown
    • Alpha isoform-specific contributions not distinguished
  4. 1995 High

    Identification of the α-subunit C-terminal TRTK-12 motif as a Ca²⁺-dependent S100B/S100A1 binding epitope revealed a calcium-signaling input that could modulate CapZ targeting or activity independently of PIP2.

    Evidence Phage display, fluorescence spectrophotometry, gel overlay, cross-linking; later NMR and crystal structures of the complex

    PMID:19452629 PMID:20053360 PMID:7540176 PMID:9416599

    Open questions at the time
    • Functional consequence of S100 binding on CapZ capping activity in cells not established
    • Whether S100 and PIP2 competition at the alpha C-terminus is physiologically relevant remains untested
  5. 1999 High

    Demonstration that CapZ controls filament length distribution and thereby cytoskeletal elasticity provided a biophysical framework for understanding CapZ's impact on tissue mechanics, while direct binding to α-actinin provided a Z-disc anchoring mechanism independent of actin.

    Evidence Quantitative filament length/rheology measurements at varying CapZ:actin ratios; fluorescence and ELISA binding assays for α-actinin interaction

    PMID:10412090 PMID:9915586

    Open questions at the time
    • Relative contribution of α-actinin vs. nebulin anchoring not resolved
    • In vivo validation of the rheological predictions lacking
  6. 2003 High

    The 2.1 Å crystal structure of CapZ revealed the α/β pseudosymmetric fold and identified the mobile C-terminal 'tentacles' as the actin-binding elements, providing a structural framework for understanding all subsequent regulatory modifications and interactions.

    Evidence X-ray crystallography of chicken sarcomeric CapZ heterodimer

    PMID:12660160

    Open questions at the time
    • No structure of CapZ bound to an actin filament barbed end
    • Conformational changes upon tentacle phosphorylation/acetylation not resolved structurally
  7. 2006 High

    The discovery that CapZ anchors PKC-βII (and later PP1α) at cardiac myofilaments, and that CapZ deficiency abolishes PKC-βII-dependent modulation of Ca²⁺ sensitivity, recast CapZ as a signaling scaffold at the Z-disc, not merely a structural cap.

    Evidence Transgenic CapZ-deficient mice, PIP2 extraction, single-myocyte isometric tension, immunoblotting

    PMID:16870209 PMID:18364747

    Open questions at the time
    • Direct binding interface between CapZ and PKC-βII/PP1α not mapped
    • Whether scaffolding is alpha- or beta-subunit dependent not resolved
  8. 2008 High

    Identifying nebulin modules 160–164 as a direct CapZ-binding partner that positions barbed ends at the Z-disc, and that nebulin knockdown displaces CapZ, resolved how thin filament length and polarity are coordinated in skeletal muscle.

    Evidence Blot overlay, solid-phase binding, tryptophan fluorescence, siRNA knockdown in chick myotubes

    PMID:18272787

    Open questions at the time
    • Structural basis of the nebulin–CapZ interface not determined
    • Whether alpha1 and alpha2 isoforms differ in nebulin binding unknown
  9. 2009 High

    Live-cell FRAP studies showed that hypertrophic stimuli (endothelin-1, phenylephrine) and mechanical strain dynamically increase CapZ exchange on actin through PIP2- and PKC-dependent pathways, establishing that CapZ capping is acutely tuned by physiological signals in cardiomyocytes.

    Evidence FRAP of GFP-CapZβ1 in neonatal cardiomyocytes with pharmacological manipulation (neomycin, chelerythrine, PMA); cyclic mechanical stretch

    PMID:19295171 PMID:23493359

    Open questions at the time
    • Specific phosphorylation site(s) responsible for increased dynamics not identified at this stage
    • Whether alpha2 dynamics parallel beta1 dynamics not tested
  10. 2016 High

    Mass spectrometry identification of CapZβ1 Ser-204 phosphorylation and Lys-199 acetylation near the actin-binding surface, regulated by PKCε and HDAC3 respectively, provided the molecular post-translational code through which hypertrophic signals control CapZ–actin binding.

    Evidence 2D gel/MS PTM mapping, FRAP with dominant-negative PKCε and HDAC inhibitors, HDAC3 myofilament immunoblotting

    PMID:27185186

    Open questions at the time
    • Whether these PTMs are sufficient individually or require combinatorial action not resolved
    • Acetyltransferase responsible for Lys-199 acetylation not identified
  11. 2015 High

    CapZ was shown to promote actin assembly on autophagosomal isolation membranes through PtdIns(3)P binding, expanding CapZ function beyond barbed-end capping to a role in membrane-shaping during autophagy.

    Evidence siRNA knockdown, latrunculin/3-MA treatment, live-cell imaging, CapZ–PtdIns(3)P binding assay

    PMID:26237647

    Open questions at the time
    • How CapZ switches from capping to promoting actin assembly on membranes not mechanistically explained
    • Whether α1 or α2 isoform is preferentially involved in autophagy unclear
  12. 2020 High

    De novo heterozygous CAPZA2 mutations were shown to cause a neurodevelopmental disorder in humans, and Drosophila rescue experiments confirmed that these variants are hypomorphic, establishing CAPZA2 as a disease gene for actin-dependent brain development.

    Evidence Human genetic analysis; Drosophila cpa-null rescue with wild-type and mutant human CAPZA2; bristle morphogenesis assay

    PMID:32338762

    Open questions at the time
    • Neuronal cell-type-specific mechanism of pathology not delineated
    • Whether loss of capping or scaffolding function drives the phenotype unknown
  13. 2024 High

    CapZ was found to transiently associate with early endosomes and its timely release is required for early-to-late endosome transition; forced CapZ retention or knockout blocks endosomal maturation and inhibits viral genome escape, revealing a non-sarcomeric trafficking role for CapZ.

    Evidence Live imaging, rapamycin-inducible tethering, CRISPR CapZ knockout, viral infection assays (ZIKV, DENV, MHV)

    PMID:38273307

    Open questions at the time
    • Molecular trigger for CapZ dissociation from maturing endosomes not identified
    • Whether this requires the alpha2 or alpha1 isoform specifically not tested
  14. 2025 High

    Mouse models of CAPZA2 haploinsufficiency and a patient-derived point mutation recapitulated the human neurodevelopmental phenotype with altered dendritic spine morphology, synaptic protein changes, and transcriptional dysregulation, providing the first mammalian in vivo disease model.

    Evidence CAPZA2+/- and CAPZA2c.G776T/+ mice; behavioral, morphological, Western blot, and single-cell RNA-seq analyses

    PMID:40659881

    Open questions at the time
    • Causal relationship between specific spine defects and behavioral phenotypes not established
    • Rescue experiments with wild-type CAPZA2 not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the high-resolution structure of CapZ bound to an actin filament barbed end; isoform-specific (α1 vs α2) functional differences in non-muscle contexts; the molecular basis by which CapZ switches between capping, scaffolding, and membrane-associated roles; and the acetyltransferase responsible for CapZβ1 Lys-199 acetylation.
  • No cryo-EM or crystal structure of CapZ–barbed-end complex
  • Alpha isoform-specific knockout studies in mammals lacking
  • Mechanism of CapZ recruitment to and release from endosomal membranes uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 7 GO:0008289 lipid binding 3
Localization
GO:0005856 cytoskeleton 8 GO:0005768 endosome 1 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-397014 Muscle contraction 5 R-HSA-162582 Signal Transduction 4 R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
ACTN2CAPZBNEBPPP1CAPRKCBRCSD1S100A1S100B
Complex memberships
CapZ (capping protein heterodimer, α2/β)

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1989 CapZ caps actin filament barbed ends with a Kd of ~0.5–1 nM, blocking both polymerization and depolymerization at the barbed (but not pointed) end, and nucleates actin polymerization at a rate proportional to the first power of CapZ concentration. The native heterodimer has a molecular weight of ~59,600 Da. No severing activity was detected. Multiple biochemical assays: pyrene-actin polymerization, critical concentration measurement, filament dilution assay, equilibrium ultracentrifugation Biochemistry High 2557904
1991 PIP2 micelles bind CapZ and completely inhibit its actin-capping and nucleation activities; other anionic phospholipids at higher concentrations also inhibit CapZ, while neutral phospholipids have no effect. This identifies phosphoinositide regulation as a mechanism for controlling CapZ activity. Multiple independent actin polymerization assays (pyrene-actin, DNase I inhibition, viscometry) with phospholipid micelles and vesicles Biochemistry High 1653607
1991 Two distinct alpha-subunit isoforms of CapZ (alpha1 and alpha2) are encoded by different single-copy genes and expressed in all tested chicken tissues. The alpha2 sequence exactly matches peptides from purified muscle CapZ alpha, establishing alpha2 as the primary muscle isoform. cDNA library screening, Northern analysis, Southern blot, peptide sequencing Cell motility and the cytoskeleton Medium 1711931
1991 CapZ caps actin filament barbed ends (not along the filament length) in a Ca2+-independent manner; both gCap39 and CapZ bind filament ends specifically as observed by direct fluorescence microscopy of individual filaments. Direct fluorescence microscopy of rhodamine-phalloidin-labeled actin filaments bound to coverslips coated with capping proteins The Journal of cell biology High 1661732
1992 The C-terminal region of the CapZ beta subunit is an actin-binding site: deletion of the COOH-terminus abolishes barbed-end binding and nucleation, and a peptide from this region binds actin monomers. A monoclonal antibody (1E5) against this region blocks CapZ–actin interaction. Deletion mutagenesis, in vitro translation, bacterial fusion protein expression, monoclonal antibody inhibition assay The Journal of cell biology High 1370838
1993 During myofibrillogenesis in cultured chicken skeletal muscle, CapZ is assembled at nascent Z-discs before actin achieves its striated pattern, consistent with CapZ directing actin filament polarity and location during I-band formation. CapZ co-localizes with A-CAM and vinculin at cardiac myocyte cell-cell junctions. Double immunofluorescence microscopy of developing myotubes and cardiac myocytes in culture Cell motility and the cytoskeleton Medium 8402953
1995 The COOH-terminal region of the CapZ alpha subunit (residues 265–276, sequence TRTK-12) binds S-100b in a Ca2+-dependent manner. This interaction is blocked by the TRTK-12 peptide and demonstrated by gel overlay and cross-linking; the motif (K/R)(L/I)XWXXIL is a consensus S-100b binding epitope. Bacteriophage peptide display library screening, fluorescence spectrophotometry, gel overlay, chemical cross-linking The Journal of biological chemistry High 7540176
1995 Inhibition of CapZ–actin interaction in developing myotubes (by anti-CapZ antibody microinjection or expression of actin-binding-deficient mutant CapZ) disrupts non-striated actin bundles and delays striated organization of both actin and alpha-actinin at Z-discs, but does not significantly affect titin or myosin organization. CapZ binds nascent Z-discs independently of actin. Monoclonal antibody microinjection, dominant-negative mutant overexpression in cultured skeletal myotubes, immunofluorescence microscopy The Journal of cell biology High 7822423
1996 S100a0 (S100A1) interacts with CapZ in a Ca2+-dependent manner via the COOH-terminal region of the CapZ alpha subunit. The TRTK-12 peptide from this region also binds phosphatidylinositol 4-monophosphate, suggesting S100a0 and polyphosphoinositides compete for the same binding site on CapZα, potentially modulating CapZ activity. Chemical cross-linking, dose-dependent peptide competition assay, fluorescence spectrophotometry Biochemical and biophysical research communications Medium 8660341
1997 The binding site for the CapZ alpha peptide TRTK-12 on S100B maps to residues near the C-terminus of the C-terminal helix and residues Val-8 to Asp-12 of the N-terminal helix of S100B, forming a patch across the dimer interface — a site that may be common to many S100 protein–protein interactions. NMR backbone assignment of Ca2+-S100B and chemical shift perturbation mapping with 15N-labeled protein Protein science High 9416599
1997 Erythrocyte CapZ (alpha1beta2 isoform) is fully functional in capping barbed ends (Kcap ~1–5 nM) and nucleating actin polymerization, yet is found exclusively in the cytosol and does not associate with the membrane skeleton, indicating barbed ends of erythrocyte actin filaments are capped by adducin rather than CapZ. Protein purification, 2D gel electrophoresis, pyrene-actin elongation and depolymerization assays, cosedimentation with membranes prepared under different ionic conditions Biochemistry High 9354614
1998 Functional CapZ heterodimer (beta-actinin) can be reconstituted from recombinant subunits expressed in E. coli: co-expression of both alpha2 and beta1 subunits is required for solubility and activity, whereas individual subunits form insoluble inclusion bodies. The beta1 subunit can refold as a single polypeptide, suggesting it acts as a molecular template for alpha2 folding. Bacterial co-expression, renaturation from inclusion bodies, actin-capping activity assays compared to native CapZ Journal of muscle research and cell motility Medium 9742448
1998 CapZ (capZ) is identified as a component of Listeria actin tails by affinity approach, localizing with cofilin, coronin, and Rac, implicating CapZ in Listeria-induced actin assembly dynamics in host cells. Affinity purification using Listeria as matrix from bovine brain extracts, peptide sequencing, immunofluorescence in infected cells Journal of cell science Medium 9730980
1999 CapZ interacts directly with alpha-actinin (a major Z-disc component) with affinity in the micromolar range; binding contacts lie in the 55 kDa repetitive domain of alpha-actinin and are weakened by phosphoinositides. This interaction is independent of actin, providing a structural anchor for thin filaments at the Z-disc. Fluorescence assays, immunochemical binding assays (ELISA), inhibition by phosphoinositides Journal of muscle research and cell motility Medium 10412090
1999 At physiological CapZ concentrations, one actin filament forms per CapZ molecule and the resulting short filaments have dramatically reduced elasticity compared to longer filaments of lower concentration, demonstrating that CapZ-mediated filament length control is a key determinant of cytoskeletal mechanical properties. Fluorescence microscopy of rhodamine-phalloidin-labeled filaments, length distribution measurement, rheological assays Cell motility and the cytoskeleton High 9915586
2000 Refolding of CapZ heterodimer from inclusion bodies is successful when both alpha2 and beta1 subunits are co-refolded; beta1 alone can refold but alpha2 alone cannot, indicating beta1 serves as a folding template for alpha2. Refolded heterodimer has actin-binding activity indistinguishable from native muscle CapZ. Inclusion body renaturation, actin-binding activity assays, biochemical characterization Protein expression and purification Medium 10648164
2003 The crystal structure of chicken CapZ (sarcomeric, including the alpha2 isoform) at 2.1 Å resolution reveals that the alpha and beta subunits are structurally similar, giving the heterodimer pseudo-2-fold rotational symmetry. A pair of mobile C-terminal extensions ('tentacles') mediates actin filament barbed-end binding, with one extension also enabling concomitant binding to another protein for filament targeting. X-ray crystallography at 2.1 Å resolution The EMBO journal High 12660160
2003 CD2 cytoplasmic tail links to the actin cytoskeleton via a chain: CD2 proline-rich tail → CMS (CD2AP)/CIN85 SH3 domains → CapZ C-terminal region. Direct binding between CMS/CIN85 and CAPZ was demonstrated by BIAcore and biochemical pulldown, and overexpression of CMS/CIN85 fragments alters T cell signaling. BIAcore surface plasmon resonance, affinity pulldown from T cell lysate, overexpression functional assays The Journal of biological chemistry Medium 12690097
2003 CapZ alpha2 subunit abundance decreases ~3-fold in human saphenous vein smooth muscle cells in response to simulated arterial hemodynamic stress, identified alongside post-translational modification changes in HSP27 and gelsolin, suggesting actin filament barbed-end capping is dynamically regulated during contractile remodeling. 2D gel electrophoresis, mass spectrometry-based proteomics (MALDI-TOF), quantitative PDQuest analysis Molecular & cellular proteomics Medium 14612593
2005 CapZIP (CapZ-interacting protein) physically interacts with CapZ in splenocytes and muscle. Phosphorylation of CapZIP at Ser-179 by MAPKAP-K2/K3, and at multiple other sites by JNK and other stress-activated kinases, triggers dissociation of CapZIP from CapZ in response to osmotic shock or anisomycin treatment in Jurkat cells. Co-immunoprecipitation, in vitro kinase assay, mass spectrometry phosphosite identification, pharmacological inhibitors (SB 203580, PD 184352) The Biochemical journal High 15850461
2005 V-1 (an ankyrin repeat protein) physically associates with CapZ-beta in PC12D cells and co-localizes in Purkinje cell soma. The V-1:CapZ association is reduced ~2 h after forskolin (cAMP elevation) treatment and recovers by 12 h, demonstrating cAMP-dependent regulation of the V-1–CapZ interaction. Co-immunoprecipitation, Western blotting, immunohistochemistry, pharmacological cAMP manipulation Biochemical and biophysical research communications Medium 15845376
2006 CapZ anchors PKC-betaII at cardiac myofilaments: myofilaments from CapZ-deficient transgenic mice or PIP2-extracted wild-type myofilaments both lack myofilament-associated PKC-betaII. PKC-betaII reduces myofilament Ca2+ sensitivity in wild-type but not CapZ-deficient myofilaments, establishing CapZ as essential for PKC-betaII-mediated myofilament regulation. Transgenic mouse model (TG-CapZ), PIP2 extraction, isometric tension measurements in single myocytes, immunoblot analysis Journal of molecular and cellular cardiology High 16870209
2008 CapZ directly and specifically interacts with the C-terminus of nebulin (modules 160–164); this binding does not affect CapZ's ability to cap actin in vitro. Knockdown of nebulin in chick skeletal myotubes reduces assembled CapZ and causes misalignment of thin filament barbed ends, suggesting nebulin positions CapZ to restrict barbed ends to the Z-disc. Blot overlay, solid-phase binding assay, tryptophan fluorescence, SPOT membrane assay, siRNA knockdown, immunofluorescence Molecular biology of the cell High 18272787
2008 PP1alpha (protein phosphatase type 1 alpha) binds cardiac myofilaments, and CapZ extraction reduces myofilament-associated PP1alpha and attenuates PP1alpha-dependent effects on myofilament Ca2+ sensitivity and actomyosin ATPase activity, indicating CapZ facilitates PP1alpha anchoring at the Z-disc for myofilament regulation. Immunoblot analysis, actomyosin MgATPase assay, CapZ extraction with PIP2, exogenous PP1alpha treatment Biochemistry and cell biology Medium 18364747
2009 NAP-22 (a neuronal presynaptic membrane protein) binds CapZ directly; NAP-22 N-terminal myristoylation is not required for this interaction. NAP-22 binding does not affect CapZ nucleation activity, suggesting the CapZ–NAP-22 complex could serve as an actin nucleation or filament anchoring site at neuronal membrane microdomains. Pull-down assay with brain-derived NAP-22 on Sepharose, mass spectrometry identification, Western blotting, recombinant protein binding assay, actin nucleation assay Journal of neuroscience research Medium 19267422
2009 Endothelin-1 and phenylephrine increase CapZ dynamics (fluorescence recovery after photobleaching) in neonatal rat ventricular myocytes, and these effects are blocked by PIP2 sequestration (neomycin) or PKC inhibition (chelerythrine), establishing that hypertrophic stimuli regulate CapZ–actin capping dynamics through PIP2- and PKC-dependent pathways. FRAP of GFP-CapZβ1 in live cardiomyocytes, pharmacological manipulation American journal of physiology. Cell physiology High 19295171
2009 The solution NMR structure of TRTK-12 (from CapZ alpha, residues 265–276) bound to Ca2+-S100A1 shows the peptide forms an amphipathic helix with W7, I10, and L11 engaging a hydrophobic pocket in S100A1 exposed only in the Ca2+-bound state. Solution NMR structure determination of S100A1–TRTK12 complex Journal of molecular biology High 19452629
2010 X-ray crystal structures of Ca2+-S100B alone (1.5 Å) and in complex with TRTK-12 (2.0 Å) show that TRTK-12 binding is dominated by Trp7 engaging a hydrophobic pocket involving helices 2 and 3 and loop 2 of S100B. TRTK-12 binding increases S100B Ca2+-binding affinity by reducing conformational dynamics in EF2, as confirmed by NMR 15N relaxation. X-ray crystallography (1.5 Å and 2.0 Å), NMR 15N relaxation Journal of molecular biology High 20053360
2010 BAG3 and Hsc70 maintain myofibrillar integrity under mechanical stress through CapZβ1: BAG3 promotes Hsc70–CapZβ1 association, facilitates proper CapZβ1 localization, and prevents CapZ ubiquitin-proteasome degradation. Loss of BAG3 leads to CapZ mislocalization and myofibrillar disruption under stretch; CapZβ2 overexpression increases myofibril vulnerability while CapZβ1 overexpression rescues bag3 knockdown phenotype. shRNA knockdown in neonatal rat cardiomyocytes, mechanical stretch assay, co-immunoprecipitation, overexpression rescue, bag3-/- mouse model Circulation research High 20884878
2010 CapZ localizes in dendritic spines and its accumulation is activity-dependent: TTX treatment reduces CapZ in spines, and high-frequency stimulation of the medial perforant path increases CapZ immunoreactivity specifically in the target dendritic layer, indicating synapse-specific regulation of CapZ redistribution in neurons. Immunostaining of brain sections and cultured hippocampal neurons, unilateral high-frequency stimulation in awake rats, 2D gel protein profiling Genes to cells Medium 20545768
2011 Reduced cardiac CapZ (transgenic mice) decreases ischemia-reperfusion injury and enhances preconditioning. Mechanistically, CapZ deficiency alters PKC isoform translocation to myofilaments: post-IR myofilament PKC-alpha is elevated but PKC-epsilon rise is attenuated, and PKC-delta and -zeta decrease rather than the changes seen in wild-type hearts. Transgenic mouse model, global ischemia-reperfusion protocol, immunoblotting of myofilament fractions, infarct size measurement Journal of molecular and cellular cardiology Medium 22155006
2013 After cyclic mechanical strain (10% at 1 Hz for 1 h) in neonatal rat ventricular myocytes, CapZ and actin dynamics increase (measured by FRAP) and return to baseline 2–3 h after stimulation ends. Expression of CapZβ1 with a C-terminal deletion mimics the strain-induced dynamic increase, implicating the beta-tentacle of CapZβ1 as the mechanosensitive element regulating thin filament capping. FRAP of GFP-CapZβ1 and actin-GFP/RFP in mechanically stimulated cardiomyocytes, dominant-negative truncation mutant Journal of applied physiology High 23493359
2015 CapZβ (specifically CapZβ knockdown) is required for autophagosomal membrane shaping: CapZ promotes actin assembly inside isolation membranes, and its knockdown causes isolation membrane and omegasome collapse. CapZ binds PtdIns(3)P (enriched in omegasomes) to stimulate local actin polymerization, and this process is PtdIns(3)P-dependent (inhibited by 3-MA or Beclin-1 knockdown). siRNA knockdown, actin polymerization inhibitor (latrunculin), PI(3)K inhibitor (3-MA), live-cell imaging, CapZ–PtdIns(3)P binding assay Nature cell biology High 26237647
2016 During phenylephrine-induced cardiac hypertrophy, CapZβ1 is phosphorylated at Ser-204 and acetylated at Lys-199 (near the actin-binding surface). Dominant-negative PKCε blunts PE-induced CapZ dynamics and reduces both modifications. Class I HDAC inhibition increases Lys-199 acetylation and CapZ dynamics; HDAC3 dissociates from myofibrils upon PE treatment, suggesting signal-dependent regulation of CapZβ1 acetylation controls myofibril growth. 2D gel electrophoresis, mass spectrometry (phosphosite and acetylation identification), FRAP of GFP-CapZβ1, dominant-negative PKCε expression, HDAC inhibitors, HDAC3 immunoblot of myofilament fractions Cellular signalling High 27185186
2016 INF2 disease mutations (E184K, S186P, R218Q) associated with FSGS increase INF2 interaction with CapZ alpha-1 (F-actin capping protein), as identified by GFP-Trap pulldown and mass spectrometry in human podocytes, suggesting dysregulated CapZ–INF2 interaction contributes to actin dynamics abnormalities in nephrotic syndrome. GFP-Trap immunoprecipitation, mass spectrometry, expression of disease mutants in podocytes Bioscience reports Medium 26764407
2019 CapZ integrates mechanical stiffness signals in cardiomyocytes via PIP2 binding and PKC-mediated phosphorylation: stiffer substrates increase CapZ FRAP kinetics (loosened actin binding), which is blocked by PIP2 reduction (neomycin) or replicated by PKC activation (PMA). Molecular simulations indicate phosphorylation at T267 of the beta-tentacle modifies PIP2–CapZ interactions. FRET confirms direct PIP2–CapZ interaction in living cells, dependent on the beta-tentacle. FRAP in living cardiomyocytes on variable-stiffness substrates, FRET, molecular dynamics simulation, PIP2 sequestration (neomycin), PKC activation (PMA), beta-tentacle deletion mutant The Journal of general physiology High 30808692
2020 Damaging heterozygous de novo mutations in CAPZA2 cause a neurodevelopmental disorder in humans (global motor delay, speech delay, intellectual disability, hypotonia, seizures). In Drosophila, loss of the single CapZ alpha ortholog (cpa) is lethal; human CAPZA2 rescues this lethality, but the two disease variants rescue at lower efficiency and cause bristle morphogenesis defects, demonstrating that these mutations impair CAPZA2 function in actin-dependent developmental processes. Human genetic analysis (de novo mutation identification), Drosophila rescue experiments (lethality assay), bristle morphogenesis assay Human molecular genetics High 32338762
2020 CAPZA2 is a positive regulator of CFTR trafficking to the plasma membrane under EPAC1 activation: CAPZA2 was identified by protein interaction profiling as an EPAC1-dependent CFTR interactor, and its reduction decreases CFTR at the PM, while INF2 reduction has the opposite effect. This identifies CAPZA2 as a novel component of cAMP/EPAC1-mediated CFTR PM stabilization. Protein interaction profiling (co-immunoprecipitation/proteomics), siRNA knockdown, PM CFTR quantification by surface biotinylation, EPAC1 activation The Biochemical journal Medium 32573649
2024 CapZ transiently associates with early endosomes (EEs) and is released upon EE maturation (transition to late endosomes, facilitated by PI(3)P-to-PI(3,5)P2 conversion). Artificial tethering of CapZ to EEs or CapZ knockout blocks early-to-late endosome transition. Both conditions inhibit flavivirus (ZIKV, DENV) and beta-coronavirus (MHV) infection by preventing viral genome escape from endocytic vesicles. Live imaging, rapamycin-inducible protein tethering system, CapZ knockout (CRISPR), Vacuolin-1 pharmacology, viral infection assays BMC biology High 38273307
2025 CAPZA2 heterozygous knockout and point-mutant (c.G776T) mice show reduced CAPZA2 in hippocampus and PFC, motor dysfunction, anxiety, spatial and non-spatial memory impairments, and social deficits. Morphological analysis reveals increased dendritic spine density, altered spine morphology in hippocampus, decreased dendritic complexity in PFC, altered PSD95 and glutamate receptor levels, and transcriptional dysregulation of neurodevelopmental and synaptic genes. CAPZA2+/- and CAPZA2c.G776T/+ mouse models, behavioral assays, morphological analysis, single-cell RNA-seq, Western blotting Communications biology High 40659881
2025 The Legionella effector RavB allosterically binds CapZ and decaps actin filaments, functionally mimicking eukaryotic CapZ-interacting proteins. This was identified by the SidBait proximity ligation approach and validated by structural and biochemical studies. SidBait proximity ligation (engineered bacterial ubiquitin ligase), structural analysis, biochemical actin decapping assay bioRxiv (preprint)preprint Medium
2025 Exercise in female mice rapidly alters CapZ–actin binding: submaximal running increases myofilament CapZIP and decreases phosphorylated CapZIP (indicating weakened CapZ–actin interaction), without changing total CapZ. CapZ-deficient transgenic mice have reduced exercise capacity, impaired actomyosin MgATPase, blunted myofilament PKC-α and -ε translocation, and decreased telethonin/Tcap with exercise, establishing CapZ as essential for the physiological cardiac exercise response. Transgenic CapZ-deficient mice, exhaustive swimming and running, actomyosin MgATPase assay, ProQ Diamond phosphorylation staining, immunoblotting of myofilament fractions FASEB journal Medium 40832763

Source papers

Stage 0 corpus · 82 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2016 ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell 1233 26777405
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
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2010 MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis. Immunology and cell biology 221 20458337
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2015 ∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis. Nature 209 26618866
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2003 The DNA sequence of human chromosome 7. Nature 188 12853948
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
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1995 Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ. The Journal of biological chemistry 121 7540176
2015 CapZ regulates autophagosomal membrane shaping by promoting actin assembly inside the isolation membrane. Nature cell biology 119 26237647
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2003 Linking the T cell surface protein CD2 to the actin-capping protein CAPZ via CMS and CIN85. The Journal of biological chemistry 96 12690097
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1998 Identification of cofilin, coronin, Rac and capZ in actin tails using a Listeria affinity approach. Journal of cell science 56 9730980
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1997 Purification and characterization of an alpha 1 beta 2 isoform of CapZ from human erythrocytes: cytosolic location and inability to bind to Mg2+ ghosts suggest that erythrocyte actin filaments are capped by adducin. Biochemistry 49 9354614
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2020 Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay. Human molecular genetics 26 32338762
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2006 Control of cardiac myofilament activation and PKC-betaII signaling through the actin capping protein, CapZ. Journal of molecular and cellular cardiology 26 16870209
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2020 Cytoskeleton regulators CAPZA2 and INF2 associate with CFTR to control its plasma membrane levels under EPAC1 activation. The Biochemical journal 19 32573649
2016 Disease causing mutations in inverted formin 2 regulate its binding to G-actin, F-actin capping protein (CapZ α-1) and profilin 2. Bioscience reports 19 26764407
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2024 The temporal association of CapZ with early endosomes regulates endosomal trafficking and viral entry into host cells. BMC biology 6 38273307
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