Sarcoplasmic reticulum histidine-rich calcium-binding protein (HRC) is a luminal SR protein that functions as a low-affinity, high-capacity calcium buffer and sensor in cardiac and skeletal muscle. HRC regulates SR calcium cycling through Ca2+-dependent interactions with both SERCA2a (the SR Ca2+-ATPase) and triadin/RyR2 (the ryanodine receptor release complex). At low SR luminal calcium, HRC preferentially binds and inhibits SERCA2a, attenuating Ca2+ uptake; as SR fills, HRC dissociates from SERCA2a and binds triadin to modulate RyR2-mediated Ca2+ release. This Ca2+-sensitive switching mechanism coordinates SR Ca2+ uptake and release during excitation-contraction coupling. HRC is phosphorylated by FAM20C at Ser96, and the Ser96Ala variant prevents this phosphorylation and is associated with increased arrhythmia susceptibility in dilated cardiomyopathy.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005509 calcium ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: HRC is a well-established calcium-binding protein with low affinity (KD ~1.9 mM) and high capacity (~200 nmol Ca2+/mg protein). The histidine-rich tandem repeats are responsible for calcium binding. This IEA annotation is consistent with the IDA evidence and is appropriate. Reason: Calcium ion binding is a core molecular function of HRC. The protein contains multiple histidine-rich acidic tandem repeats that bind calcium with high capacity (PMID:2037293, PMID:17526652). This annotation is correct. Supporting Evidence: PMID:2037293 Histidine-rich calcium binding protein (HRC) is a luminal sarcoplasmic reticulum (SR) protein of 165 kDa identified by virtue of its ability to bind 125I-labeled low-density lipoprotein with high affinity PMID:17526652 The histidine-rich Ca-binding protein (HRC) is an SR component that binds to triadin and may affect Ca release through the ryanodine receptor file:human/HRC/HRC-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0033018 sarcoplasmic reticulum lumen | IEA GO_REF:0000044 | ACCEPT | Summary: HRC localizes to the SR lumen in cardiac and skeletal muscle. This is its primary site of function where it interacts with SERCA2a and triadin. Multiple studies confirm this localization. Reason: SR lumen localization is well-established for HRC. The protein contains a signal peptide targeting it to the secretory pathway and resides within the SR lumen where it performs its calcium buffering and regulatory functions (PMID:11504710, PMID:17526652). Supporting Evidence: PMID:11504710 While HRC resides in the lumen of the sarcoplasmic reticulum, the physiological function of HRC is largely unknown PMID:17526652 The present study shows that HRC may mediate part of its regulatory effects by binding directly to sarco(endo)plasmic reticulum Ca-ATPase type 2 (SERCA2) in cardiac muscle |
| GO:0005515 protein binding | IPI PMID:17924338 A novel dominant mutation in plakoglobin causes arrhythmogen... | REMOVE | Summary: This generic protein binding annotation from a plakoglobin mutation study is not informative about HRC's specific molecular function. The term is too broad and uninformative. Reason: GO:0005515 (protein binding) is an uninformative term that does not describe HRC's actual functional interactions. HRC has specific binding partners (SERCA2a, triadin) that are better captured by more specific terms. This annotation adds no value to understanding HRC function. Supporting Evidence: PMID:17924338 A novel dominant mutation in plakoglobin causes arrhythmogenic right ventricular cardiomyopathy. |
| GO:0005515 protein binding | IPI PMID:24805197 The arrhythmogenic human HRC point mutation S96A leads to sp... | REMOVE | Summary: This study investigated HRC interactions in the context of the S96A variant and calcium buffering. Generic protein binding is not informative. Reason: GO:0005515 (protein binding) is uninformative. The specific interactions of HRC (with SERCA2a and triadin) are better described by more specific MF terms like ATPase binding and transmembrane transporter binding. Supporting Evidence: PMID:24805197 2014 May 5. The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca(2+) release due to an impaired ability to buffer store Ca(2+). |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: This high-throughput interactome mapping study provides generic protein binding evidence. Not informative for HRC annotation. Reason: GO:0005515 is uninformative. High-throughput interaction data does not provide specific mechanistic insight into HRC function. The specific binding partners are better annotated with more specific terms. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HRC localizes to the sarcoplasmic reticulum, which is a specialized form of smooth ER in muscle cells. While technically correct, the more specific term GO:0033018 (SR lumen) is more appropriate for this protein. Reason: While HRC is indeed in the ER system (as SR is specialized smooth ER), the more specific annotation to SR lumen (GO:0033018) is more informative. This broader annotation can be retained but is not a core localization term for HRC. |
| GO:0005515 protein binding | IPI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | REMOVE | Summary: This key study examined HRC interactions with triadin and demonstrated diminished interaction of Ala96 HRC with triadin. However, generic protein binding is uninformative. Reason: GO:0005515 is uninformative. The specific HRC-triadin interaction is better captured by the transmembrane transporter binding annotation or could be annotated more specifically. Supporting Evidence: PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein. |
| GO:1903169 regulation of calcium ion transmembrane transport | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | ACCEPT | Summary: This study used transgenic mice expressing human HRC variants and demonstrated that HRC regulates SR calcium handling. Ala96 HRC decreased cardiomyocyte contractility and Ca2+ kinetics, with increased Ca2+ waves despite reduced SR Ca2+ load. Reason: HRC regulates calcium transmembrane transport by modulating both SERCA2a-mediated uptake and RyR2-mediated release. This is a core biological process for HRC (PMID:24125847, PMID:17526652). Supporting Evidence: PMID:24125847 Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC PMID:17526652 HRC may play a key role in the regulation of SR Ca cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross talk between SR Ca uptake and release in the heart |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: This Reactome annotation reflects HRC's localization for FAM20C-mediated phosphorylation. The SR lumen is a more specific and accurate term for HRC localization in muscle. Reason: While technically correct (SR is specialized ER), GO:0033018 (SR lumen) is more specific and informative for HRC. This annotation can be retained as non-core. |
| GO:0002027 regulation of heart rate | IMP PMID:18617481 The Ser96Ala variant in histidine-rich calcium-binding prote... | KEEP AS NON CORE | Summary: This study associated the HRC Ser96Ala variant with ventricular arrhythmias in DCM patients. While HRC dysfunction affects heart rhythm, this is an indirect phenotypic consequence of its SR calcium regulation function. Reason: Heart rate regulation is a downstream consequence of HRC's role in SR calcium handling rather than a direct molecular function. The annotation is supported by clinical data showing arrhythmia association (PMID:18617481), but this represents a pleiotropic phenotype. Supporting Evidence: PMID:18617481 the Ser96Ala polymorphism exhibited a statistically significant correlation with the occurrence of life-threatening ventricular arrhythmias |
| GO:0010460 positive regulation of heart rate | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | KEEP AS NON CORE | Summary: This annotation is based on IGI evidence from transgenic mouse studies. The Ala96 HRC variant showed increased propensity to arrhythmias, which may affect heart rate. This is a downstream phenotypic effect. Reason: This annotation reflects phenotypic consequences of HRC dysfunction rather than its core molecular function. HRC's effect on heart rate is mediated through SR calcium regulation. Supporting Evidence: PMID:24125847 Parallel in vivo studies revealed ventricular ectopy on short-term isoproterenol challenge and increased (4-fold) propensity to arrhythmias |
| GO:0045823 positive regulation of heart contraction | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | MODIFY | Summary: HRC regulates cardiac muscle contraction through its control of SR calcium cycling. The direction of effect (positive or negative) depends on HRC levels and phosphorylation status. Reason: The term should be the parent term GO:0045822 (regulation of heart contraction) since HRC can have both positive and negative effects depending on context. HRC overexpression decreases contractility while appropriate HRC function maintains normal contraction. Proposed replacements: regulation of heart contraction Supporting Evidence: PMID:24125847 Ala96 HRC decreased (25% to 30%) cardiomyocyte contractility and Ca2+ kinetics compared with Ser96 HRC PMID:17526652 HRC overexpression in transgenic mouse hearts was associated with decreased rates of SR Ca uptake and delayed relaxation |
| GO:1901844 regulation of cell communication by electrical coupling involved in cardiac conduction | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | MARK AS OVER ANNOTATED | Summary: This is an overly specific term. The study demonstrated arrhythmias and delayed afterdepolarizations but not specifically electrical coupling between cardiomyocytes. Reason: This term is too specific. While HRC dysfunction leads to arrhythmias, the mechanism involves SR calcium leak and delayed afterdepolarizations rather than direct effects on gap junction-mediated electrical coupling between cells. Supporting Evidence: PMID:24125847 stress conditions (5 Hz plus isoproterenol) induced aftercontractions (65% in Ala96 versus 12% in Ser96) and delayed afterdepolarizations (70% in Ala96 versus 20% in Ser96) |
| GO:1901899 positive regulation of relaxation of cardiac muscle | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | MODIFY | Summary: HRC affects cardiac muscle relaxation through its regulation of SR calcium uptake via SERCA2a. However, the evidence shows HRC overexpression delays relaxation rather than promoting it. Reason: The evidence suggests HRC regulates relaxation but the direction is context-dependent. HRC overexpression delays relaxation. A more appropriate term would be the parent GO:0055118 (regulation of relaxation of cardiac muscle). Proposed replacements: regulation of relaxation of cardiac muscle Supporting Evidence: PMID:17526652 HRC overexpression in transgenic mouse hearts was associated with decreased rates of SR Ca uptake and delayed relaxation PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein. |
| GO:0005509 calcium ion binding | IDA PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | ACCEPT | Summary: This IDA annotation confirms HRC's calcium binding capacity through direct assays including 45Ca2+ overlay and Stains-all staining. Reason: Calcium ion binding is the core molecular function of HRC. The study directly demonstrated calcium binding using 45Ca2+ overlay assays (PMID:24125847). Supporting Evidence: PMID:24125847 Enriched SR membrane fractions were isolated from Ser96 and Ala96 hearts, and different amounts (25, 50, and 100 ΞΌg) of protein were analyzed by using SDSβPAGE |
| GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | ACCEPT | Summary: This annotation is highly relevant to HRC's core function. HRC binds triadin and modulates RyR2-mediated calcium release from the SR. The Ala96 variant shows increased Ca2+ sparks and waves due to diminished triadin interaction. Reason: This is a core biological process for HRC. The protein regulates SR calcium release through its Ca2+-dependent interaction with triadin, which affects RyR2 stability (PMID:24125847, PMID:11504710). Supporting Evidence: PMID:24125847 The underlying mechanisms involved diminished interaction of Ala96 HRC with triadin, affecting ryanodine receptor (RyR) stability PMID:11504710 Our data suggest that HRC may play a role in the regulation of Ca(2+) release from the sarcoplasmic reticulum by interaction with triadin |
| GO:0030018 Z disc | IDA PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | UNDECIDED | Summary: Z disc localization is unexpected for HRC, which is an SR luminal protein. This may reflect immunostaining of nearby SR elements or cross-reactivity. Reason: HRC is well-established as an SR luminal protein with a signal peptide. Z disc localization would be inconsistent with its known signal peptide and luminal interactions. This annotation may reflect proximity of SR to Z discs in cardiomyocytes rather than true Z disc localization. Further investigation needed. Supporting Evidence: PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated with the human Ser96Ala genetic variant of histidine-rich calcium-binding protein. |
| GO:0051480 regulation of cytosolic calcium ion concentration | IGI PMID:24125847 Abnormal calcium cycling and cardiac arrhythmias associated ... | ACCEPT | Summary: HRC regulates cytosolic calcium concentration indirectly through its effects on SR calcium uptake and release. This is a downstream consequence of SR calcium regulation. Reason: While HRC acts within the SR, its regulation of SR calcium handling directly affects cytosolic calcium concentrations during excitation-contraction coupling (PMID:24125847). Supporting Evidence: PMID:24125847 the frequency of Ca2+ waves was significantly higher (10-fold), although SR Ca2+ load was reduced (by 27%) in Ala96 HRC cells |
| GO:0005515 protein binding | IPI PMID:17526652 Histidine-rich Ca-binding protein interacts with sarcoplasmi... | REMOVE | Summary: This study demonstrated specific HRC interactions with SERCA2a and triadin. Generic protein binding is uninformative; the specific interactions are captured by other terms. Reason: GO:0005515 is uninformative. The specific HRC-SERCA2a and HRC-triadin interactions demonstrated in this paper are better captured by GO:0051117 (ATPase binding) and GO:0044325 (transmembrane transporter binding). Supporting Evidence: PMID:17526652 Histidine-rich Ca-binding protein interacts with sarcoplasmic reticulum Ca-ATPase. |
| GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion | TAS PMID:17526652 Histidine-rich Ca-binding protein interacts with sarcoplasmi... | ACCEPT | Summary: This term precisely describes HRC's core function - regulating cardiac contraction through control of SR calcium release and uptake. Reason: This is a core biological process for HRC that integrates its calcium binding, SERCA2a interaction, and triadin/RyR2 modulation into its physiological role in cardiac muscle (PMID:17526652). Supporting Evidence: PMID:17526652 HRC may play a key role in the regulation of SR Ca cycling through its direct interactions with SERCA2 and triadin, mediating a fine cross talk between SR Ca uptake and release in the heart |
| GO:0033018 sarcoplasmic reticulum lumen | TAS PMID:11504710 Interaction of HRC (histidine-rich Ca(2+)-binding protein) a... | ACCEPT | Summary: This TAS annotation to SR lumen is well-supported by direct evidence. HRC is established as an SR luminal protein. Reason: SR lumen is the correct and specific localization for HRC. This is its primary site of function (PMID:11504710, PMID:17526652). Supporting Evidence: PMID:11504710 While HRC resides in the lumen of the sarcoplasmic reticulum |
| GO:0044325 transmembrane transporter binding | IPI PMID:17526652 Histidine-rich Ca-binding protein interacts with sarcoplasmi... | ACCEPT | Summary: HRC binds SERCA2a, a transmembrane calcium transporter. This annotation reflects the specific HRC-SERCA2a interaction. Reason: HRC directly binds SERCA2a (a transmembrane Ca2+ transporter) through its histidine- and glutamic acid-rich domain. This interaction is Ca2+-dependent and regulates SR calcium uptake (PMID:17526652). Supporting Evidence: PMID:17526652 HRC may mediate part of its regulatory effects by binding directly to sarco(endo)plasmic reticulum Ca-ATPase type 2 (SERCA2) in cardiac muscle |
| GO:0051117 ATPase binding | IPI PMID:17526652 Histidine-rich Ca-binding protein interacts with sarcoplasmi... | ACCEPT | Summary: HRC binds SERCA2a, which is a P-type Ca2+-ATPase. The interaction domain is mapped to HRC residues 320-460 and SERCA2 residues 74-90. Reason: HRC directly binds SERCA2a (Ca2+-ATPase) through defined interaction domains. This is a core molecular function that mediates HRC's regulation of SR calcium uptake (PMID:17526652). Supporting Evidence: PMID:17526652 This interaction involves the histidine- and glutamic acid-rich domain of HRC (320-460 aa) and the part of the NH(2)-terminal cation transporter domain of SERCA2 (74-90 aa) that projects into the SR lumen |
| GO:0005509 calcium ion binding | TAS PMID:2037293 cDNA and genomic cloning of HRC, a human sarcoplasmic reticu... | ACCEPT | Summary: The original cloning paper established HRC as a calcium-binding protein based on its histidine-rich repeats and biochemical properties. Reason: This is the foundational evidence for HRC's calcium binding function. The protein was identified based on its calcium-binding properties (PMID:2037293). Supporting Evidence: PMID:2037293 Histidine-rich calcium binding protein (HRC) is a luminal sarcoplasmic reticulum (SR) protein of 165 kDa |
| GO:0006936 muscle contraction | TAS PMID:2037293 cDNA and genomic cloning of HRC, a human sarcoplasmic reticu... | KEEP AS NON CORE | Summary: Muscle contraction is implied by HRC's SR localization and calcium-binding function. This is a broad term; more specific terms like GO:0010881 better capture HRC's role. Reason: While HRC is involved in muscle contraction through its SR calcium regulation, this broad term is less informative than more specific terms. Retain as non-core since the connection is indirect through calcium regulation. Supporting Evidence: PMID:2037293 cDNA and genomic cloning of HRC, a human sarcoplasmic reticulum protein, and localization of the gene to human chromosome 19 and mouse chromosome 7. |
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