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10 sources retrieved · Most recent: April 2026 · Index updated 14 days ago
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STAC
SH3 and cysteine rich domain
Chromosome 3 · 3p22.3-p22.2
NCBI Gene: 6769Ensembl: ENSG00000144681.11HGNC: HGNC:11353UniProt: B4DR96
24PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingcalcium channel regulator activityskeletal muscle contractionpositive regulation of voltage-gated calcium channel activitystage 5 chronic kidney diseasediabetic nephropathymale reproductive organ cancerFollicular Cyst
✦AI Summary

STAC (SH3 and cysteine rich domain) is a calcium channel modulator protein consisting of conserved cysteine-rich and SH3 domains 1. The protein functions primarily as an adaptor that regulates voltage-gated calcium channel trafficking and activity. In skeletal muscle, STAC3 is essential for excitation-contraction coupling, mediating mechanical coupling between the L-type calcium channel CaV1.1 and the ryanodine receptor RyR1 23. STAC proteins associate with the IQ domain in the C-terminus of CaV1 channels through conserved C1 and SH3 domains 4. Mechanistically, STAC proteins suppress calcium-dependent inactivation (CDI) of L-type calcium channels by interfering with calcium-calmodulin feedback regulation 54. In neurons, STAC2 expression increases substantially postnatally in forebrain and cerebellum, suggesting developmental regulation of L-type channel calcium signaling 5. Mutations in STAC3 cause congenital myopathy and severe muscle disease by disrupting the mechanical coupling essential for muscle contraction 2. While STAC3's role in skeletal muscle is well-characterized, neuronal STAC isoforms (STAC1 and STAC2) appear to function as tuning regulators of neuronal L-type calcium channels, though their complete functional significance in brain remains incompletely understood.

Sources cited
1
STAC is a neuron-specific protein with cysteine-rich and SH3 domains, located on human chromosome 3p22-p24
PMID: 9465308
2
STAC3 is critical for mechanical coupling between CaV1.1 and RyR1 in skeletal muscle excitation-contraction coupling; mutations cause congenital myopathy
PMID: 34129875
3
STAC3 is an essential component of skeletal muscle EC coupling and links CaV1.1 and RyR1
PMID: 30543836
4
STAC proteins interact with the IQ domain in the C-terminus of CaV channels; this interaction inhibits calcium-dependent inactivation
PMID: 29363593
5
STAC proteins suppress calcium-dependent inactivation of L-type calcium channels CaV1.2 and CaV1.3; STAC2 expression increases postnatally in forebrain and cerebellum
PMID: 30201773
Disease Associationsⓘ20
stage 5 chronic kidney diseaseOpen Targets
0.31Weak
diabetic nephropathyOpen Targets
0.31Weak
male reproductive organ cancerOpen Targets
0.29Weak
Follicular CystOpen Targets
0.25Weak
placental retentionOpen Targets
0.23Weak
ovarian neoplasmOpen Targets
0.21Weak
response to placeboOpen Targets
0.21Weak
generalised epilepsyOpen Targets
0.21Weak
adolescent idiopathic scoliosisOpen Targets
0.20Weak
Abnormality of limbsOpen Targets
0.19Weak
immune system diseaseOpen Targets
0.19Weak
dislocationOpen Targets
0.16Weak
ovarian dysfunctionOpen Targets
0.14Weak
allergic rhinitisOpen Targets
0.11Weak
seasonal allergic rhinitisOpen Targets
0.11Weak
brain aneurysmOpen Targets
0.06Suggestive
benign chondrogenic neoplasmOpen Targets
0.04Suggestive
bipolar disorderOpen Targets
0.03Suggestive
glomerulonephritisOpen Targets
0.03Suggestive
non-small cell lung carcinomaOpen Targets
0.03Suggestive
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
HLA-GProtein interaction99%KIR2DL1Protein interaction91%KIR2DL4Protein interaction91%KIR3DL1Protein interaction91%KIR3DL2Protein interaction91%SORBS1Protein interaction91%
Tissue Expression6 tissues
Brain
100%
Lung
77%
Bone Marrow
16%
Ovary
15%
Liver
14%
Heart
6%
Gene Interaction Network
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STACHLA-GKIR2DL1KIR2DL4KIR3DL1KIR3DL2SORBS1
PROTEIN STRUCTURE
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PDB6B25 · 2.39 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
1.18LoF Tolerant
pLIⓘ
0.00Tolerant
Observed/Expected LoF0.90 [0.69–1.18]
RankingsWhere STAC stands among ~20K protein-coding genes
  • #13,320of 20,598
    Most Researched24
  • #12,378of 17,882
    Most Constrained (LOEUF)1.18
Genes detectedSTAC
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
The adaptive brain: aging and neurocognitive scaffolding.
PMID: 19035823
Annu Rev Psychol · 2009
1.00
2
Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence.
PMID: 29514064
Cell Metab · 2018
0.90
3
Human and mouse chromosomal mapping of Stac, a neuron-specific protein with an SH3 domain.
PMID: 9465308
Genomics · 1998
0.80
4
How does it STAC up? Revisiting the scaffolding theory of aging and cognition.
PMID: 25143069
Neuropsychol Rev · 2014
0.70
5
Structure and function of STAC proteins: Calcium channel modulators and critical components of muscle excitation-contraction coupling.
PMID: 34129875
J Biol Chem · 2021
0.60