Regucalcin (SMP30) is a multifunctional calcium-binding protein and gluconolactonase enzyme that catalyzes the penultimate step in vitamin C biosynthesis. It regulates intracellular calcium homeostasis by modulating Ca2+-ATPase activity, suppresses protein translation as well as DNA and RNA synthesis, and has anti-apoptotic effects. Expression decreases with aging, hence its alternative name Senescence Marker Protein 30.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004341 gluconolactonase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation correctly identifies the core enzymatic function. Strongly supported by experimental evidence in PMID:16585534 showing gluconolactonase activity is essential for vitamin C biosynthesis. This is a primary molecular function of the protein. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md 1. **Primary biochemical function:** Rat Rgn encodes regucalcin/SMP30, a **metal-dependent gluconolactonase/lactonase (EC 3.1.1.17)** with a **six-bladed Ξ²βpropeller** active site coordinating a divalent metal (Glu18/Asn154/Asp204; Asn103 important for catalysis). file:rat/Rgn/Rgn-deep-research-falcon.md A central, experimentally supported biochemical activity of regucalcin/SMP30 is **gluconolactonase (EC 3.1.1.17)** activity, requiring a **divalent metal ion** (e.g., **Zn2+** and **Mn2+** are cited as activators) and showing activity on multiple **aldonolactones** in vitro (e.g., D/LβgluconoβΞ³βlactone, D/LβgulonoβΞ³βlactone, D/LβgalactonoβΞ³βlactone). |
| GO:0005509 calcium ion binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation correctly identifies calcium binding as a core function. Strongly supported by experimental evidence dating back to PMID:699201 and confirmed by structural studies. Essential for both its enzymatic activity and calcium homeostasis regulatory functions. Falcon deep research notes regucalcin is a Ca2+-binding/Ca2+-signaling protein but is explicitly NOT an EF-hand protein; the divalent metal (including Ca2+/Mg2+) is coordinated at the catalytic active site (Glu18/Asn154/Asp204). Reason: Calcium binding is retained on direct biochemical/structural evidence (classic rat regucalcin Ca2+-binding studies; active-site divalent-metal coordination); note that the IBA itself is stale β the current PANTHER PAINT release no longer carries an IBD for this term in PTHR10907. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTHR10907 Β· regucalcin/SMP30 family (PAINT) SOURCE STALE OR MISSING No IBD for GO:0005509 remains in the current PTHR10907 PAINT slice (snapshot 20251127); the remaining IBDs at PTN004208435 are GO:0004341, nucleus, cytoplasm, and GO:0050848 only. PAINT has withdrawn or re-scoped this function assertion; the ACCEPT here rests on the direct rat biochemical evidence, not on the IBA. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Regucalcin is also widely described as a **multifunctional Ca2+-signaling regulator** (not an EFβhand protein), acting as a cytoplasmic regulator and capable of **nuclear translocation**, with inhibitory effects on multiple kinases/phosphatases and on DNA/RNA/protein synthesis, thereby influencing cell-cycle progression and apoptosis sensitivity in various rat cell systems. |
| GO:0019853 L-ascorbic acid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation correctly identifies involvement in vitamin C biosynthesis. Strongly supported by PMID:16585534 showing this enzyme catalyzes the penultimate step. This is a core biological function. Reason: The ascorbate-biosynthesis role is retained on direct experimental evidence (PMID:16585534; SMP30/GNL knockout mice develop scurvy); note that the IBA itself is stale β the current PANTHER PAINT release no longer carries an IBD for this term in PTHR10907. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTHR10907 Β· regucalcin/SMP30 family (PAINT) SOURCE STALE OR MISSING No IBD for GO:0019853 remains in the current PTHR10907 PAINT slice (snapshot 20251127); the remaining IBDs at PTN004208435 are GO:0004341, nucleus, cytoplasm, and GO:0050848 only. PAINT has withdrawn or re-scoped this process assertion; the ACCEPT here rests on the direct rodent experimental evidence, not on the IBA. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md **Ascorbate/vitamin C pathway role (in nonβprimates):** SMP30/GNL is implicated in the ascorbic acid biosynthesis pathway by catalyzing formation of the **Ξ³βlactone ring** from **Lβgulonate** (i.e., producing **LβgulonoβΞ³βlactone**, which is then converted to ascorbic acid by downstream enzymes). Genetic/physiological support includes **SMP30/GNL knockout mice** developing **scurvy** on vitamin Cβdeficient diets. |
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Duplicate of the IBA annotation above, both are correct. IEA based on InterPro domains aligns with experimental evidence. Calcium binding is a well-established core function. |
| GO:0030234 enzyme regulator activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: GO:0030234 (enzyme regulator activity) is a highly generic MF parent term that conveys little specific information. The distinct enzyme regulatory activities of Rgn are already captured by more specific annotations elsewhere in this review (e.g., ATPase regulator activity GO:0060590, negative regulation of translation/aminoacyl-tRNA synthetase, regulation of nitric-oxide synthase, regulation of DNA/RNA synthesis). Accepting this generic term as a core function adds no informative value and per project guidelines uninformative parent terms should not be retained as core. Reason: Generic enzyme regulator activity is superseded by the specific regulator-activity terms already annotated; retaining it as core would be an over-annotation. Supporting Evidence: file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles |
| GO:0004341 gluconolactonase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Another correct annotation of gluconolactonase activity. IEA from multiple sources confirms this core enzymatic function. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic localization is well-established. Protein is predominantly cytoplasmic. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | REMOVE | Summary: This is too general. The protein has specific gluconolactonase activity (GO:0004341) which is already annotated. This broad parent term adds no informative value. |
| GO:0019853 L-ascorbic acid biosynthetic process | IEA GO_REF:0000043 | ACCEPT | Summary: Duplicate annotation of vitamin C biosynthesis with IEA evidence. This core function is well-established. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | REMOVE | Summary: Too general. The protein specifically binds calcium (GO:0005509) and zinc (GO:0008270) ions, which are already annotated with more specific terms. |
| GO:0010558 negative regulation of macromolecule biosynthetic process | IDA PMID:2280766 Effect of calcium-binding protein regucalcin on hepatic prot... | MODIFY | Summary: This term is too general. The experimental evidence specifically shows inhibition of aminoacyl-tRNA synthetase activity, affecting protein synthesis. Should be replaced with GO:0017148 (negative regulation of translation) or GO:0031127 (negative regulation of aminoacyl-tRNA ligase activity) for specificity. Proposed replacements: negative regulation of translation Supporting Evidence: PMID:2280766 Effect of calcium-binding protein regucalcin on hepatic protein synthesis: inhibition of aminoacyl-tRNA synthetase activity. file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles |
| GO:1903011 negative regulation of bone development | IMP PMID:11129957 Role of endogenous regucalcin in protein tyrosine phosphatas... | KEEP AS NON CORE | Summary: This IMP annotation cites PMID:11129957, whose cached abstract concerns regucalcin regulation of protein tyrosine phosphatase activity in cloned rat hepatoma cells (H4-II-E) and does not mention bone; the cache is abstract-only, so the specific supporting evidence cannot be re-verified from the accessible text and the curator's full-text reading is deferred to. The term itself is genuinely established for Rgn by the parallel IDA annotation citing PMID:12239582 (bone loss induced in regucalcin transgenic rats), so the annotation is kept, but as a secondary systemic phenotype rather than a core function, consistent with the treatment of the IDA row for the same term. Reason: The bone-loss phenotype of regucalcin overexpression is real but is a downstream physiological consequence of regucalcin's Ca2+-homeostasis and signaling-suppressor roles, not a core molecular function; aligned with the KEEP_AS_NON_CORE call on the IDA annotation of the same term. The abstract-only cache of PMID:11129957 prevents verifying this row's specific assay, so per curation guidelines the curator is not overruled. Supporting Evidence: PMID:11129957 Role of endogenous regucalcin in protein tyrosine phosphatase regulation in the cloned rat hepatoma cells (H4-II-E). |
| GO:1903011 negative regulation of bone development | IDA PMID:12239582 Role of endogenous regucalcin in bone metabolism: bone loss ... | KEEP AS NON CORE | Summary: Duplicate annotation showing bone loss in Rgn transgenic rats. Secondary effect rather than core function. Supporting Evidence: PMID:12239582 Role of endogenous regucalcin in bone metabolism: bone loss is induced in regucalcin transgenic rats. |
| GO:1903625 negative regulation of DNA catabolic process | IDA PMID:2001740 Inhibitory effect of calcium-binding protein regucalcin on C... | ACCEPT | Summary: Evidence shows inhibition of Ca2+-activated DNA fragmentation. This anti-apoptotic function is part of the broader cellular protection role. Supporting Evidence: PMID:2001740 The Ca2+ (10 microM)-activated DNA fragmentation was inhibited by the presence of Ca2(+)-binding protein regucalcin isolated from rat liver cytosol. The inhibitory effect of regucalcin was complete at 0.5 microM. |
| GO:0010867 positive regulation of triglyceride biosynthetic process | IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an... | KEEP AS NON CORE | Summary: Evidence from overexpression studies shows enhanced lipid production. This metabolic regulatory function is supported but represents a secondary function. Supporting Evidence: PMID:16817230 Overexpression of regucalcin enhances glucose utilization and lipid production in cloned rat hepatoma H4-II-E cells: Involvement of insulin resistance. |
| GO:0010907 positive regulation of glucose metabolic process | IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an... | KEEP AS NON CORE | Summary: Enhanced glucose utilization shown in overexpression studies. Secondary metabolic regulatory function. Supporting Evidence: PMID:16817230 Overexpression of regucalcin enhances glucose utilization and lipid production in cloned rat hepatoma H4-II-E cells: Involvement of insulin resistance. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:15806309 Overexpression of regucalcin suppresses apoptotic cell death... | ACCEPT | Summary: Well-documented anti-apoptotic effect in hepatoma cells treated with sulforaphane. This cytoprotective function is important for cell survival. Supporting Evidence: PMID:15806309 This study demonstrates that sulforaphane induces cell death and apoptosis in the cloned rat hepatoma H4-II-E cells, and that overexpression of regucalcin suppresses sulforaphane-induced apoptotic cell death which is partly mediated through caspase-3. |
| GO:0045723 positive regulation of fatty acid biosynthetic process | IDA PMID:16817230 Overexpression of regucalcin enhances glucose utilization an... | KEEP AS NON CORE | Summary: Related to lipid metabolism regulation shown in the same study. Secondary metabolic function. Supporting Evidence: PMID:16817230 Overexpression of regucalcin enhances glucose utilization and lipid production in cloned rat hepatoma H4-II-E cells: Involvement of insulin resistance. |
| GO:0050680 negative regulation of epithelial cell proliferation | IDA PMID:16142398 Overexpression of regucalcin suppresses cell proliferation o... | ACCEPT | Summary: Suppression of kidney epithelial cell proliferation demonstrated. Part of the general anti-proliferative regulatory function. Supporting Evidence: PMID:16142398 Cell numbers of transfectants were significantly suppressed as compared with that of wild- and mock-type. |
| GO:0001822 kidney development | IEP PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coo... | KEEP AS NON CORE | Summary: Expression pattern during kidney development shown. While expressed during development, this is not a core function but reflects tissue expression pattern. Supporting Evidence: PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coordinated up-regulation with tissue maturation and gradual down-regulation with aging. |
| GO:0001889 liver development | IEP PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coo... | KEEP AS NON CORE | Summary: Expression pattern during liver development. Not a core function but reflects developmental expression pattern. Supporting Evidence: PMID:8794449 Gene regulation of senescence marker protein-30 (SMP30): coordinated up-regulation with tissue maturation and gradual down-regulation with aging. |
| GO:0004341 gluconolactonase activity | IDA PMID:16585534 Senescence marker protein 30 functions as gluconolactonase i... | ACCEPT | Summary: Direct experimental evidence proving gluconolactonase activity and its essential role in vitamin C biosynthesis. Knockout mice lacking this enzyme develop scurvy. This is a core enzymatic function. Supporting Evidence: PMID:16585534 SMP30 purified from the rat liver had lactonase activity toward various aldonolactones, such as d- and l-glucono-delta-lactone, d- and l-gulono-gamma-lactone, and d- and l-galactono-gamma-lactone, with a requirement for Zn(2+) or Mn(2+) as a cofactor. Furthermore, in SMP30 knockout mice, no GNL activity was detectable in the liver. Thus, we conclude that SMP30 is a unique GNL in the liver. file:rat/Rgn/Rgn-deep-research-falcon.md A central, experimentally supported biochemical activity of regucalcin/SMP30 is **gluconolactonase (EC 3.1.1.17)** activity, requiring a **divalent metal ion** (e.g., **Zn2+** and **Mn2+** are cited as activators) and showing activity on multiple **aldonolactones** in vitro (e.g., D/LβgluconoβΞ³βlactone, D/LβgulonoβΞ³βlactone, D/LβgalactonoβΞ³βlactone). |
| GO:0007283 spermatogenesis | IDA PMID:23615721 Sperm parameters and epididymis function in transgenic rats ... | KEEP AS NON CORE | Summary: Evidence shows involvement in sperm maturation and motility. While documented, this is a tissue-specific function rather than core. Supporting Evidence: PMID:23615721 Apr 23. Sperm parameters and epididymis function in transgenic rats overexpressing the Ca2+-binding protein regucalcin: a hidden role for Ca2+ in sperm maturation? Correia S(1), Oliveira PF, Guerreiro PM, Lopes G, Alves MG, CanΓ‘rio AV, Cavaco JE, Socorro S. |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:16167335 Overexpression of regucalcin suppresses apoptotic cell death... | ACCEPT | Summary: Duplicate annotation showing anti-apoptotic effects in kidney epithelial cells. Consistent cytoprotective function. Supporting Evidence: PMID:16167335 Overexpression of regucalcin suppresses apoptotic cell death in cloned normal rat kidney proximal tubular epithelial NRK52E cells: change in apoptosis-related gene expression. |
| GO:0097421 liver regeneration | IEP PMID:7759556 Enhanced expression of calcium-binding protein regucalcin mR... | KEEP AS NON CORE | Summary: Enhanced expression during liver regeneration. While involved, this is a context-specific response rather than core function. Supporting Evidence: PMID:7759556 Enhanced expression of calcium-binding protein regucalcin mRNA in regenerating rat liver. |
| GO:1901318 negative regulation of flagellated sperm motility | IDA PMID:23615721 Sperm parameters and epididymis function in transgenic rats ... | KEEP AS NON CORE | Summary: Overexpression affects sperm motility. Tissue-specific effect related to calcium regulation in sperm. Supporting Evidence: PMID:23615721 Apr 23. Sperm parameters and epididymis function in transgenic rats overexpressing the Ca2+-binding protein regucalcin: a hidden role for Ca2+ in sperm maturation? Correia S(1), Oliveira PF, Guerreiro PM, Lopes G, Alves MG, CanΓ‘rio AV, Cavaco JE, Socorro S. |
| GO:1902679 negative regulation of RNA biosynthetic process | IMP PMID:12397604 Role of endogenous regucalcin in nuclear regulation of regen... | ACCEPT | Summary: Evidence shows suppression of RNA synthesis in regenerating liver. Part of the core regulatory function on nucleic acid biosynthesis and cell proliferation control. Supporting Evidence: PMID:12397604 The present study demonstrates that endogenous regucalcin has a suppressive effect on the enhancement of RNA synthesis activity in the nucleus of regenerating rat liver with proliferative cells. file:rat/Rgn/Rgn-deep-research-falcon.md Regucalcin is also widely described as a **multifunctional Ca2+-signaling regulator** (not an EFβhand protein), acting as a cytoplasmic regulator and capable of **nuclear translocation**, with inhibitory effects on multiple kinases/phosphatases and on DNA/RNA/protein synthesis, thereby influencing cell-cycle progression and apoptosis sensitivity in various rat cell systems. |
| GO:2000279 negative regulation of DNA biosynthetic process | IMP PMID:11500948 Regulatory role of endogenous regucalcin in the enhancement ... | ACCEPT | Summary: Well-documented suppression of DNA synthesis in hepatoma cells. This is part of the core regulatory function on nucleic acid biosynthesis and cell proliferation control. Supporting Evidence: PMID:11500948 The present study demonstrates that endogenous regucalcin plays a suppressive role in the enhancement of nuclear DNA synthesis with proliferative cells. |
| GO:1903052 obsolete positive regulation of proteolysis involved in protein catabolic process | IDA PMID:1513338 Calcium-binding protein regucalcin increases calcium-indepen... | MODIFY | Summary: This GO term is obsolete (verified via OLS; term_replaced_by GO:0045732). The experimental evidence (PMID:1513338) shows regucalcin increases Ca2+-independent proteolytic activity in rat liver cytosol and activates a neutral cysteinyl-proteinase, i.e. it positively regulates protein catabolism. MODIFY to the official replacement term GO:0045732 (positive regulation of protein catabolic process), which preserves the original BP aspect. Proposed replacements: positive regulation of protein catabolic process Supporting Evidence: PMID:1513338 The present findings suggest that regucalcin increases proteolytic activity in rat liver cytosol, and that regucalcin may activate Ca(2+)-independent neutral cysteinyl-proteinase. |
| GO:0001889 liver development | IEP PMID:9546611 Expression of calcium-binding protein regucalcin mRNA in fet... | KEEP AS NON CORE | Summary: Duplicate annotation of expression during liver development. Non-core developmental expression pattern. Supporting Evidence: PMID:9546611 Expression of calcium-binding protein regucalcin mRNA in fetal rat liver is stimulated by calcium administration. |
| GO:0045019 negative regulation of nitric oxide biosynthetic process | IMP PMID:12686401 Inhibitory role of regucalcin in the regulation of nitric ox... | ACCEPT | Summary: Inhibits nitric oxide synthase activity in brain. Part of the broader regulatory function on cellular signaling. Supporting Evidence: PMID:12686401 The present study demonstrates that endogenous regucalcin has an inhibitory effect on NO synthase activity in the brain cytosol of young and aged rats. file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles |
| GO:0004341 gluconolactonase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Another duplicate gluconolactonase annotation. This core function is well-established. |
| GO:0004341 gluconolactonase activity | ISO GO_REF:0000096 | ACCEPT | Summary: Another duplicate gluconolactonase annotation based on orthology. Consistent with experimental evidence. |
| GO:0019853 L-ascorbic acid biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: Another duplicate of vitamin C biosynthesis annotation. Consistent with experimental evidence. |
| GO:0019853 L-ascorbic acid biosynthetic process | ISO GO_REF:0000096 | ACCEPT | Summary: Another duplicate vitamin C biosynthesis annotation based on orthology. Well-supported core function. |
| GO:0005509 calcium ion binding | ISO GO_REF:0000096 | ACCEPT | Summary: Another duplicate calcium binding annotation with ISO evidence. Calcium binding is a core function. |
| GO:0008270 zinc ion binding | ISS GO_REF:0000024 | ACCEPT | Summary: Correct annotation. Zinc is a cofactor for gluconolactonase activity as shown in PMID:16585534. The protein can use Zn2+ or Mn2+ as cofactors for its enzymatic activity. |
| GO:0008270 zinc ion binding | ISO GO_REF:0000096 | ACCEPT | Summary: Duplicate annotation with different evidence code. Zinc binding is confirmed as a cofactor for enzymatic activity. |
| GO:0005509 calcium ion binding | IDA PMID:699201 Purification of calcium binding substance from soluble fract... | ACCEPT | Summary: Direct experimental evidence from the original 1978 paper identifying this as a calcium-binding protein. This is foundational evidence for a core molecular function. Supporting Evidence: PMID:699201 Purification of calcium binding substance from soluble fraction of normal rat liver. |
| GO:0005634 nucleus | ISS GO_REF:0000024 | ACCEPT | Summary: Nuclear localization is supported by functional studies showing regulation of nuclear processes (DNA/RNA synthesis). Valid cellular component. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | ACCEPT | Summary: Duplicate cytoplasmic localization annotation. Well-supported. |
| GO:0006874 intracellular calcium ion homeostasis | IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc... | ACCEPT | Summary: Direct evidence for regulation of calcium homeostasis through Ca2+-ATPase modulation in mitochondria. This is a core biological function. Supporting Evidence: PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria, suggesting its role in the regulation of heart mitochondrial function. file:rat/Rgn/Rgn-deep-research-falcon.md Positions regucalcin as a multifunctional suppressor that localizes in cytoplasm and nucleus; maintains intracellular Ca2+ homeostasis by activating Ca2+ pumps in plasma membrane, mitochondria, and ER; inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression; summarizes rat liver, kidney, prostate, and hepatoma studies showing anti-proliferative and homeostatic roles |
| GO:0032781 positive regulation of ATP-dependent activity | IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc... | MODIFY | Summary: Evidence shows increased Ca2+-ATPase activity in heart mitochondria. The existing term GO:0032781 (positive regulation of ATP-dependent activity) is a biological_process term that is too general. The data directly demonstrate that regucalcin acts as an activator of the Ca2+-ATPase, better captured by the molecular_function term GO:0060590 (ATPase regulator activity). Note this is an intentional cross-aspect MODIFY from BP to MF; the activator role on the ATPase enzyme is a molecular function and is more informative than the generic BP term. Proposed replacements: ATPase regulator activity Supporting Evidence: PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitochondria of normal and regucalcin transgenic rats. |
| GO:0050848 regulation of calcium-mediated signaling | IDA PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitoc... | ACCEPT | Summary: Regulation of calcium signaling through Ca2+-ATPase modulation and calcium binding. Core regulatory function. Supporting Evidence: PMID:16786169 This study demonstrates that regucalcin has an activating effect on Ca2+-ATPase in rat heart mitochondria, suggesting its role in the regulation of heart mitochondrial function. |
| GO:0005634 nucleus | ISO GO_REF:0000096 | ACCEPT | Summary: Duplicate nuclear localization based on orthology. Consistent with functional evidence. |
| GO:0005737 cytoplasm | ISO GO_REF:0000096 | ACCEPT | Summary: Another duplicate cytoplasmic localization based on orthology. Consistent with other evidence. |
| GO:0005739 mitochondrion | IEA | NEW | Summary: mitochondrion identified from core_functions analysis Reason: This cellular component term reflects regucalcin's mitochondrial localization where it regulates Ca2+-ATPase activity and mitochondrial calcium homeostasis. Supporting Evidence: PMID:16786169 Regucalcin increases Ca2+-ATPase activity in the heart mitochondria of normal and regucalcin transgenic rats. |
| GO:0017148 negative regulation of translation | IEA | NEW | Summary: Core function of regucalcin in protein synthesis regulation Reason: Regucalcin inhibits aminoacyl-tRNA synthetase activity, thereby negatively regulating translation. This is one of its core regulatory functions but was missing from existing annotations. Supporting Evidence: PMID:2280766 The present results suggest that regucalcin can regulate protein synthesis in liver cells. |
| GO:0004857 enzyme inhibitor activity | IDA PMID:2280766 Effect of calcium-binding protein regucalcin on hepatic prot... | NEW | Summary: NEW annotation. Regucalcin acts as a direct inhibitor of multiple cellular enzymes: it markedly decreases hepatic aminoacyl-tRNA synthetase activity (PMID:2280766) and the deep research summarizes its inhibition of kinases, phosphatases, nitric oxide synthase, cysteinyl protease, and aminoacyl-tRNA synthetase. This enzyme-inhibitor molecular function underlies the suppressor roles captured in this review's core functions but is missing from the existing GOA molecular function annotations. Reason: Enzyme inhibitor activity (GO:0004857) is the molecular function behind regucalcin's documented suppression of aminoacyl-tRNA synthetase and other target enzymes; adding it grounds the translation- and proliferation- suppressor core functions in an annotated molecular function rather than leaving them without an MF anchor. The root-level term is deliberate, because no child of GO:0004857 fits. Regucalcin's inhibition is not confined to one enzyme class - the documented targets span aminoacyl-tRNA synthetase, protein kinases, protein phosphatases, nitric oxide synthase and a cysteinyl protease - and GO has no aminoacyl-tRNA synthetase inhibitor child to carry the best-characterised case, so any specific child would understate the activity while asserting a specificity the evidence does not support. Supporting Evidence: PMID:2280766 the protein (1.0-2.0 microM) caused a remarkable decrease in the enzyme activity. file:rat/Rgn/Rgn-deep-research-falcon.md inhibits kinases, phosphatases, nitric oxide synthase, cysteinyl protease, aminoacyl-tRNA synthetase, DNA/RNA synthesis, and cell-cycle progression |
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Q: What determines the nuclear versus cytoplasmic distribution of regucalcin and how does this affect its function?
Q: How does regucalcin interact with calcium-binding proteins and calcium channels to modulate cellular calcium?
Q: What role does regucalcin play in aging and cellular senescence, and how is its expression regulated?
Experiment: Live-cell calcium imaging to study the effects of regucalcin on calcium dynamics in different cell types
Experiment: Proteomics analysis to identify regucalcin interacting partners and calcium-dependent protein interactions
Experiment: Subcellular fractionation and imaging to determine regucalcin localization and translocation during calcium signaling
Experiment: Analysis of regucalcin expression and function during aging using longitudinal studies in animal models
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