Affinage

STAC2

SH3 and cysteine-rich domain-containing protein 2 · UniProt Q6ZMT1

Length
411 aa
Mass
45.0 kDa
Annotated
2026-04-28
22 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

STAC2 is an adaptor protein that modulates voltage-gated calcium channel function and bone cell signaling. It binds the II-III cytoplasmic loop and IQ domain of L-type calcium channels (CaV1.1, CaV1.2, CaV1.3) via its tandem SH3 domains and a linker segment between the PKC C1 and SH3 domains, thereby suppressing calcium-dependent inactivation (CDI) of L-type but not non-L-type currents in neurons and heterologous cells (PMID:25548159, PMID:29363593, PMID:30201773). In adrenal chromaffin cells, genetic deletion of Stac2 alters CaV isoform composition—upregulating R-type (CaV2.3) currents—and impairs excitation-secretion coupling by disrupting functional vesicle coupling to P/Q-type channels (PMID:42020143). In osteoclast precursors, STAC2 physically interacts with RANK and Btk/Tec kinases to inhibit NF-κB/MAPK signaling and suppress osteoclastogenesis, with its transcription activated by ASH1L-mediated H3K4 trimethylation at the STAC2 promoter (PMID:29348675, PMID:38431690).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2010 Medium

    The question of where STAC2 is expressed was addressed by showing it marks specific sensory neuron subtypes—nonpeptidergic nociceptors, TrkB+ neurons, and a proprioceptive subpopulation—in dorsal root ganglia, establishing it as a neuronally expressed adaptor with cell-type specificity.

    Evidence Microarray profiling of knock-in mouse DRG with in situ hybridization and immunostaining

    PMID:20736085

    Open questions at the time
    • Functional consequence of STAC2 expression in these sensory neuron subtypes was not tested
    • No loss-of-function analysis in DRG neurons
  2. 2014 High

    The first functional role of STAC2 was established: it binds CaV1.2 and dramatically slows current inactivation, placing STAC proteins as modulators of L-type calcium channel gating.

    Evidence Patch-clamp electrophysiology with co-expression of fluorescently tagged STAC2 and CaV1.2 in tsA201 cells

    PMID:25548159

    Open questions at the time
    • Molecular determinants of the STAC2–CaV interaction were unknown
    • Endogenous relevance not yet demonstrated
  3. 2017 High

    Structural determination of the STAC2 tandem-SH3 domains and their complex with the CaV1 II-III loop revealed the atomic basis of the interaction, showing a rigid SH3 interdomain interface and identifying the binding site for excitation-contraction coupling.

    Evidence X-ray crystallography (up to 1.2 Å) with mutagenesis and functional EC coupling assays in myotubes

    PMID:29078335

    Open questions at the time
    • Full-length STAC2–channel complex structure not resolved
    • Contribution of the C1 domain and linker region to channel modulation not yet mapped
  4. 2018 High

    Multiple studies converged to define STAC2's dual binding sites on CaV channels (II-III loop via SH3 domains, IQ domain via overlapping calmodulin binding site) and the sufficiency of a ~100-residue linker segment for CDI suppression, while also revealing a completely distinct role: STAC2 physically interacts with RANK and Btk/Tec kinases to suppress NF-κB/MAPK signaling and osteoclastogenesis.

    Evidence Chimeric CaV1.2/2.1 channels with alanine mutagenesis and patch-clamp in dysgenic myotubes; domain-deletion constructs in hippocampal neurons and tsA201 cells; co-immunoprecipitation and signaling assays in osteoclast precursors

    PMID:29348675 PMID:29363593 PMID:29467163 PMID:30201773

    Open questions at the time
    • Whether CDI suppression and RANK signaling inhibition operate in the same cell types was unclear
    • Structural basis of STAC2 linker–channel interaction not determined
    • In vivo relevance of STAC2 in osteoclast biology awaited genetic models
  5. 2022 Medium

    NMR-based binding studies confirmed direct SH3 domain–II-III loop peptide interaction with isoform-specific differences between STAC2 and STAC3, and mutagenesis of the analogous linker region showed it controls channel kinetics and colocalization at membrane junctions.

    Evidence NMR spectroscopy with purified SH3 domains and II-III loop peptides; site-directed mutagenesis with electrophysiology and immunofluorescence in CaV1.1/STAC3 double-KO myotubes

    PMID:35481653 PMID:36161458

    Open questions at the time
    • STAC2-specific linker mutation effects were inferred from STAC3 cross-isoform analogy rather than direct STAC2 mutagenesis
    • Full thermodynamic characterization of STAC2–channel binding not completed
  6. 2024 Medium

    The transcriptional control of STAC2 was defined: ASH1L methyltransferase binds the STAC2 promoter and activates transcription via H3K4me3, and conditional Ash1l deletion in osteoclast progenitors reduces STAC2 expression and potentiates osteoclastogenesis, providing in vivo genetic validation of the STAC2–RANK axis.

    Evidence ChIP for ASH1L and H3K4me3 at the STAC2 locus, conditional knockout mice, in vitro osteoclastogenesis assays

    PMID:38431690

    Open questions at the time
    • Direct rescue by STAC2 re-expression in Ash1l-KO osteoclast progenitors not shown
    • Whether other ASH1L targets contribute to the osteoclast phenotype was not excluded
  7. 2026 High

    Genetic deletion of Stac2 in mouse chromaffin cells demonstrated that endogenous STAC2 controls CaV isoform composition and excitation-secretion coupling: loss of Stac2 upregulates R-type currents, increases excitability, and impairs catecholamine release by disrupting vesicle coupling to P/Q-type channels.

    Evidence Stac2 knockout mice, patch-clamp electrophysiology with intracellular calcium buffering, carbon fiber amperometry

    PMID:42020143

    Open questions at the time
    • Mechanism by which STAC2 selectively suppresses CaV2.3 surface expression is unknown
    • Whether STAC2 loss affects secretory coupling in neurons (not just chromaffin cells) is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of STAC2's linker-mediated CDI suppression, how STAC2 regulates CaV isoform composition at the surface, whether the calcium channel and RANK signaling functions intersect in any cell type, and the physiological consequences of STAC2 loss in the nervous system.
  • No full-length STAC2–CaV complex structure exists
  • No Stac2 neuronal knockout phenotype reported
  • Relationship between channel modulation and bone signaling roles is unexplored

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 2
Partners
ASH1LBTKCACNA1CCACNA1DCACNA1STECTNFRSF11A

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 STAC2 (and STAC3) bind to CaV1.2 and greatly slow the rate of current inactivation; STAC3 acts as an essential chaperone for CaV1.1 trafficking to the plasma membrane in non-muscle cells, while STAC2 acts similarly on CaV1.2 modulation. Fluorescently tagged constructs in tsA201 cells, patch-clamp electrophysiology, co-expression of Stac proteins with CaV isoforms Proceedings of the National Academy of Sciences of the United States of America High 25548159
2017 Crystal structures of STAC tandem-SH3 domains (including STAC2) reveal a rigid interdomain interface; the SH3 domains bind the II-III linker connecting transmembrane repeats II and III of CaV1 channels, and a crystal structure of the complex with STAC2 was determined. A disease-associated STAC3 mutation abolishes this interaction without misfolding the SH3 domains. X-ray crystallography (up to 1.2 Å resolution), mutagenesis, functional EC coupling assays in myotubes Proceedings of the National Academy of Sciences of the United States of America High 29078335
2018 STAC1, STAC2, and STAC3 associate with the IQ domain in the C-terminus of CaV1.2 (residues 1641-1668) and thereby inhibit calcium-dependent inactivation (CDI) of CaV1.2; the interaction overlaps with the Ca/calmodulin C-lobe contact site, and substitution of the CaV1.2 IQ domain with that of CaV2.1 abolishes both STAC association and CDI inhibition. CaV1.2/2.1 chimeras expressed in dysgenic myotubes, alanine mutagenesis, patch-clamp electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 29363593
2018 STAC2 is a RANK ligand-inducible protein that physically interacts with RANK and inhibits formation of the RANK signaling complex (containing Gab2 and PLCγ2), thereby suppressing RANK-mediated NF-κB and MAPK activation; STAC2 also interacts with Btk/Tec and limits Btk/Tec-mediated PLCγ2 phosphorylation, negatively regulating osteoclast formation. Co-immunoprecipitation, overexpression and knockdown in osteoclast precursors, NF-κB/MAPK signaling assays, PLCγ2 phosphorylation assays Cell death and differentiation Medium 29348675
2018 Stac2 (and Stac1, Stac3) interact with the II-III loop of CaV1.1, specifically requiring residues in the critical domain (720-764/5); for Stac3, the first SH3 domain (not the PKC C1 domain) is required for this interaction, and binding to the critical domain parallels the ability to support EC coupling. Colocalization assays in tsA201 cells, co-expression in dysgenic myotubes with chimeric CaV1 constructs, deletion/domain mutagenesis The Journal of general physiology Medium 29467163
2018 Overexpression of Stac2 (and Stac1, Stac3) eliminates Ca2+-dependent inactivation (CDI) of L-type (CaV1.2, CaV1.3) but not non-L-type currents in rat neonatal hippocampal neurons and tsA201 cells; a ~100 residue linker segment between the PKC C1 and SH3_1 domains of Stac proteins is sufficient to suppress CDI; Stac2 protein levels increase substantially in adult forebrain/cerebellum compared to neonate. Overexpression in rat hippocampal neurons and tsA201 cells, patch-clamp electrophysiology, domain-deletion constructs, Western blotting The Journal of neuroscience High 30201773
2010 STAC2 is expressed in a distinct, mutually exclusive subset of dorsal root ganglia neurons from STAC1, marking a subset of nonpeptidergic nociceptors, all TrkB+ neurons, and a subpopulation of proprioceptive neurons, establishing STAC2 as a molecular marker of specific primary sensory neuron subtypes. Affymetrix microarrays on trkA(trkC/trkC) knock-in mice DRG, in situ hybridization/immunostaining for cell-type markers Gene expression patterns Medium 20736085
2022 Both STAC3 and the neuronal isoform STAC2 interact directly with a peptide sequence in the CaV1.1 II-III loop via residues in their SH3 domains, with isoform-specific differences in the interaction suggesting STAC3 has distinct biophysical features relevant to skeletal muscle EC coupling. NMR spectroscopy, peptide binding assays with purified SH3 domain proteins and II-III loop peptides Protein science Medium 35481653
2022 A triple mutation in the STAC3 linker region (ETLAAA), analogous to a mutation that abolishes STAC2's inhibitory effect on CDI of CaV1.3, accelerates CaV1.1 activation and inactivation kinetics and disrupts STAC3 colocalization with CaV1.1 at SR/membrane junctions, implicating the same linker region of STAC2 in CDI inhibition of CaV1.3. Site-directed mutagenesis, patch-clamp electrophysiology, calcium imaging in CaV1.1/STAC3 double-knockout myotubes, immunofluorescence colocalization Journal of cellular physiology Medium 36161458
2024 ASH1L histone methyltransferase binds the STAC2 promoter and activates STAC2 transcription via H3K4 trimethylation; conditional deletion of Ash1l in osteoclast progenitors reduces STAC2 expression and potentiates osteoclastogenesis, placing STAC2 downstream of ASH1L in a pathway restricting RANK-mediated osteoclast formation. Chromatin immunoprecipitation (ChIP), conditional knockout mice, in vitro osteoclastogenesis assays, histone methylation analysis Cell death and differentiation Medium 38431690
2024 miR-34b-5p directly regulates STAC2 expression; inhibition of miR-34b-5p promotes osteogenic differentiation of rat bone marrow mesenchymal stem cells, and modulating the miR-34b-5p/STAC2 axis attenuates the pro-osteogenic effects of low-frequency sinusoidal electromagnetic fields. miRNA mimic/inhibitor transfection in BMSCs, miRNA sequencing, in vivo OVX rat model with microCT and histology Communications biology Low 39284881
2026 Genetic deletion of Stac2 in mouse chromaffin cells causes a ~2-fold increase in R-type (CaV2.3) current density, shifts whole-cell calcium current voltage dependence of activation to more negative potentials (calcium-dependent effect), decreases action potential threshold, increases excitability, and reduces catecholamine vesicle exocytosis by impairing functional coupling of vesicles to P/Q-type channels—demonstrating that endogenous Stac2 regulates CaV isoform composition and excitation-secretion coupling. Stac2 genetic knockout mice, patch-clamp electrophysiology, intracellular calcium buffering manipulation, carbon fiber amperometry for exocytosis The Journal of physiology High 42020143

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Transcriptome profiling revealed multiple genes and ECM-receptor interaction pathways that may be associated with breast cancer. Cellular & molecular biology letters 265 31182966
2014 Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proceedings of the National Academy of Sciences of the United States of America 72 25548159
2017 Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proceedings of the National Academy of Sciences of the United States of America 57 29078335
2015 Right ventricular myocardial biomarkers in human heart failure. Journal of cardiac failure 55 25725476
2018 STAC proteins associate to the IQ domain of CaV1.2 and inhibit calcium-dependent inactivation. Proceedings of the National Academy of Sciences of the United States of America 40 29363593
1997 The tannin-degrading species Streptococcus gallolyticus and Streptococcus caprinus are subjective synonyms. International journal of systematic bacteriology 33 9226925
2018 Stac proteins associate with the critical domain for excitation-contraction coupling in the II-III loop of CaV1.1. The Journal of general physiology 32 29467163
2018 STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex. Cell death and differentiation 27 29348675
2018 Stac Proteins Suppress Ca2+-Dependent Inactivation of Neuronal l-type Ca2+ Channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 30201773
2020 Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis. Cancers 25 32971738
2010 stac1 and stac2 genes define discrete and distinct subsets of dorsal root ganglia neurons. Gene expression patterns : GEP 21 20736085
2021 Two Novel Bacillus Strains (subtilis and simplex Species) with Promising Potential for the Biocontrol of Zymoseptoria tritici, the Causal Agent of Septoria Tritici Blotch of Wheat. BioMed research international 12 34195272
2022 STAC3 determines the slow activation kinetics of CaV 1.1 currents and inhibits its voltage-dependent inactivation. Journal of cellular physiology 9 36161458
2024 The histone methyltransferase ASH1L protects against bone loss by inhibiting osteoclastogenesis. Cell death and differentiation 8 38431690
2016 RWCFusion: identifying phenotype-specific cancer driver gene fusions based on fusion pair random walk scoring method. Oncotarget 7 27506935
2022 Molecular interactions of STAC proteins with skeletal muscle dihydropyridine receptor and excitation-contraction coupling. Protein science : a publication of the Protein Society 3 35481653
2024 Identifying Key Drivers in the Pathogenesis of Martorell Hypertensive Ischaemic Leg Ulcer: A Comparative Analysis with Chronic Venous Leg Ulcer. Acta dermato-venereologica 2 38813744
2024 Low frequency sinusoidal electromagnetic fields promote the osteogenic differentiation of rat bone marrow mesenchymal stem cells by modulating miR-34b-5p/STAC2. Communications biology 2 39284881
2024 COADREADx: A comprehensive algorithmic dissection of colorectal cancer unravels salient biomarkers and actionable insights into its discrete progression. PeerJ 2 39484215
2018 Identification of differentially expressed genes and typical fusion genes associated with three subtypes of breast cancer. Breast cancer (Tokyo, Japan) 2 30446971
2026 Stac2 genetic deletion alters mouse chromaffin cells' CaV channel composition, increases membrane excitability and reduces vesicle exocytosis. The Journal of physiology 0 42020143
2025 [A multi-molecular predictive model for lymph node metastasis in papillary thyroid carcinoma based on machine learning algorithms]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences 0 41656803