Affinage

GCA

Grancalcin · UniProt P28676

Length
217 aa
Mass
24.0 kDa
Annotated
2026-06-10
100 papers in source corpus 3 papers cited in narrative 3 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Grancalcin (GCA) acts as a calcium-binding signaling scaffold and secreted modulator that potentiates innate immune and stress-response pathways across distinct cellular contexts (PMID:30929559, PMID:26648480, PMID:37949676). In chronic myeloid leukemia cells, GCA activates the ubiquitin ligase TRAF6 to drive Lys63-linked ubiquitination of ULK1, stabilizing and activating ULK1 to promote autophagy and thereby conferring imatinib resistance (PMID:30929559). In plasmacytoid dendritic cells, GCA directly binds TLR9 and positively regulates TLR9-driven type I IFN production, IRF7 nuclear localization, NF-κB activation, and MAPK activation (PMID:26648480). GCA is also secreted by bone marrow-derived immune cells, which home to the hippocampus and cortex via CCR10, where secreted GCA competitively binds microglial LRP1 to inhibit phagocytic clearance of amyloid-β and exacerbate Alzheimer's disease pathology; hematopoietic GCA ablation or GCA-neutralizing antibody treatment improved outcomes in mouse models (PMID:37949676). Beyond these three contexts, the structural basis of GCA's interactions and its calcium-dependence have not been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 3 steps
  1. 2016 Medium

    Established GCA as a direct binding partner of TLR9 and a positive regulator of innate immune signaling, linking this calcium-binding protein to nucleic-acid sensing for the first time.

    Evidence Yeast two-hybrid and overexpression co-IP for interaction, plus siRNA knockdown with NF-κB/IRF7 reporters and cytokine ELISA in plasmacytoid dendritic cells

    PMID:26648480

    Open questions at the time
    • Interaction shown only in overexpression system without endogenous reciprocal validation
    • No structural basis for the GCA–TLR9 interaction
    • Calcium-dependence of the interaction not tested
  2. 2019 Medium

    Placed GCA upstream of an autophagy-driving ubiquitination cascade, explaining how it promotes drug resistance in leukemia.

    Evidence siRNA knockdown, reciprocal co-IP, ubiquitination assays, and autophagy flux assays in CML cell lines and patient samples

    PMID:30929559

    Open questions at the time
    • No structural validation of the GCA–TRAF6 interaction
    • Mechanism by which GCA activates TRAF6 ligase activity not defined
    • Not independently replicated
  3. 2023 Medium

    Identified GCA as a secreted factor that impairs microglial amyloid-β clearance via LRP1 competition, defining a peripheral-immune contribution to Alzheimer's pathology.

    Evidence Bone marrow transplantation, hematopoietic-specific knockout, recombinant GCA injection, LRP1 competitive binding assay, microglial phagocytosis assays, and neutralizing antibody treatment in AD mouse models

    PMID:37949676

    Open questions at the time
    • LRP1 binding site and competition stoichiometry not resolved
    • Mechanism of GCA secretion not defined
    • Single lab; awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether the three reported functions reflect a single unifying biochemical activity of GCA, and how its penta-EF-hand calcium binding governs each, remains unresolved.
  • No structural model of GCA in complex with any partner
  • Calcium-dependence of binding events not experimentally linked across contexts
  • No integration of intracellular scaffold versus secreted functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005576 extracellular region 1
Pathway
R-HSA-168256 Immune System 1 R-HSA-9612973 Autophagy 1
Partners
LRP1TLR9TRAF6ULK1

Evidence

Reading pass · 3 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Grancalcin (GCA) activates TRAF6 ubiquitin ligase activity, inducing Lys63-linked ubiquitination of ULK1, which stabilizes and activates ULK1 to promote autophagy, thereby driving imatinib resistance in chronic myeloid leukemia. siRNA knockdown, co-immunoprecipitation, ubiquitination assays, autophagy flux assays in CML cell lines and patient samples Autophagy Medium 30929559
2016 Grancalcin (GCA) directly binds TLR9 (demonstrated by yeast two-hybrid and co-immunoprecipitation in an overexpression system) and positively regulates TLR9-mediated type I IFN production, cytokine/chemokine secretion, IRF7 nuclear localization, NF-κB activation, and MAPK activation in plasmacytoid dendritic cells; siRNA-mediated knockdown of GCA reduced these downstream signaling outputs. Yeast two-hybrid, co-immunoprecipitation (overexpression system), siRNA knockdown, reporter assays for NF-κB/IRF7, cytokine ELISA in plasmacytoid dendritic cells European journal of immunology Medium 26648480
2023 Bone marrow-derived GCA+ immune cells secrete grancalcin, which competitively binds to LRP1 in microglia, inhibiting microglial phagocytosis and clearance of amyloid-β, thereby potentiating Alzheimer's disease neuropathology; CCR10 mediates preferential homing of GCA+ cells to the hippocampus and cortex. Genetic ablation of GCA in the hematopoietic compartment improved cognitive function, and GCA-neutralizing antibody treatment reduced AD progression in mouse models. Bone marrow transplantation, stereotaxic injection of recombinant GCA protein, hematopoietic-specific genetic knockout, competitive binding assay for LRP1, phagocytosis assays in microglia, cognitive behavioral tests in AD mouse models, GCA-neutralizing antibody treatment Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 37949676

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA). Clinical and experimental rheumatology 255 11579707
2000 The complete nucleotide sequence of the mitochondrial genome of sugar beet (Beta vulgaris L.) reveals a novel gene for tRNA(Cys)(GCA). Nucleic acids research 239 10871408
2023 Disease stratification in GCA and PMR: state of the art and future perspectives. Nature reviews. Rheumatology 94 37308659
2016 Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): A nested case-control analysis. Seminars in arthritis and rheumatism 80 28040244
1993 Peptide-regulated guanylate cyclase pathways in rat colon: in situ localization of GCA, GCC, and guanylin mRNA. The American journal of physiology 78 8103637
2002 Progressive cardiac hypertrophy and dysfunction in atrial natriuretic peptide receptor (GC-A) deficient mice. Heart (British Cardiac Society) 73 11907014
1990 Epidemiology of biopsy-proven giant cell arteritis (GCA). Journal of internal medicine 73 2324677
2019 GCA links TRAF6-ULK1-dependent autophagy activation in resistant chronic myeloid leukemia. Autophagy 52 30929559
1995 Structure of a single-cytidine hairpin loop formed by the DNA triplet GCA. Nature structural biology 52 7583654
2021 5'-tiRNA-Cys-GCA regulates VSMC proliferation and phenotypic transition by targeting STAT4 in aortic dissection. Molecular therapy. Nucleic acids 49 34513311
2008 IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk. European journal of human genetics : EJHG 48 18285833
2007 Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer causes & control : CCC 47 17206530
1991 Antithrombin Vicenza, Ala 384 to Pro (GCA to CCA) mutation, transforming the inhibitor into a substrate. British journal of haematology 47 1998601
2019 The utility of ESR, CRP and platelets in the diagnosis of GCA. BMC rheumatology 45 31008443
2020 Probability-based algorithm using ultrasound and additional tests for suspected GCA in a fast-track clinic. RMD open 42 32994361
2007 Management guidelines and outcome measures in giant cell arteritis (GCA). Clinical and experimental rheumatology 42 18021519
2011 Successful use of tocilizumab in polymyalgic onset biopsy positive GCA with large vessel involvement. BMJ case reports 41 22693300
2009 Natriuretic Peptide Signaling via Guanylyl Cyclase (GC)-A: An Endogenous Protective Mechanism of the Heart. Current cardiology reviews 39 20066148
2009 Tongue necrosis as first symptom of giant cell arteritis (GCA). Clinical rheumatology 36 19277817
2012 Association of NOS2 and potential effect of VEGF, IL6, CCL2 and IL1RN polymorphisms and haplotypes on susceptibility to GCA--a simultaneous study of 130 potentially functional SNPs in 14 candidate genes. Rheumatology (Oxford, England) 35 22258388
2019 Decreased Expression of Negative Immune Checkpoint VISTA by CD4+ T Cells Facilitates T Helper 1, T Helper 17, and T Follicular Helper Lineage Differentiation in GCA. Frontiers in immunology 31 31379838
2019 Giant Cell Arteritis (GCA): Pathogenesis, Clinical Aspects and Treatment Approaches. Current rheumatology reviews 30 30827250
2000 Clinical features of GCA/PMR. Clinical and experimental rheumatology 29 10948748
2000 Laboratory investigations useful in the evaluation of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Clinical and experimental rheumatology 29 10948756
2012 Glycyrrhizic acid (GCA) as 11β-hydroxysteroid dehydrogenase inhibitor exerts protective effect against glucocorticoid-induced osteoporosis. Journal of bone and mineral metabolism 28 23274351
2009 Expression of guanylyl cyclase (GC)-A and GC-B during brain development: evidence for a role of GC-B in perinatal neurogenesis. Endocrinology 28 19837875
2011 Guanylyl cyclase (GC)-A and GC-B activities in ventricles and cardiomyocytes from failed and non-failed human hearts: GC-A is inactive in the failed cardiomyocyte. Journal of molecular and cellular cardiology 27 22133375
1998 The hypotrichous ciliate Euplotes octocarinatus has only one type of tRNACys with GCA anticodon encoded on a single macronuclear DNA molecule. Nucleic acids research 26 9753721
2007 An investigation on the polymorphisms of two DNA repair genes and susceptibility to ESCC and GCA of high-incidence region in northern China. Molecular biology reports 24 18046624
2012 Systematic review of the literature and a case report informing biopsy-proven giant cell arteritis (GCA) with normal C-reactive protein. Clinical rheumatology 23 22820967
1995 Prevalence of gca, a gene involved in synthesis of A-band common antigen polysaccharide in Pseudomonas aeruginosa. Clinical and diagnostic laboratory immunology 22 8548534
2015 MMP-3 can distinguish isolated PMR from PMR with GCA: A retrospective study regarding PMR and GCA in Japan. Modern rheumatology 20 26156043
2019 Validating a diagnostic GCA ultrasonography service against temporal artery biopsy and long-term clinical outcomes. Clinical rheumatology 19 31576487
2007 Plastid tRNA genes trnC-GCA and trnN-GUU are essential for plant cell development. The Plant journal : for cell and molecular biology 19 17573798
2000 Classification/diagnostic criteria for GCA/PMR. Clinical and experimental rheumatology 19 10948747
1994 Sodium status affects GC-B natriuretic peptide receptor mRNA levels, but not GC-A or C receptor mRNA levels, in the sheep kidney. Clinical science (London, England : 1979) 18 7913429
2023 Bone Marrow-Derived GCA+ Immune Cells Drive Alzheimer's Disease Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 17 37949676
2021 Incidence, survival, and diagnostic trends in GCA across seven decades in a North American population-based cohort. Seminars in arthritis and rheumatism 17 34644662
2016 A Retrospective Study of Chinese Patients With Giant Cell Arteritis (GCA): Clinical Features and Factors Associated With Severe Ischemic Manifestations. Medicine 17 27043686
2014 A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA. PloS one 17 25409453
2022 The tRNA-Cys-GCA Derived tsRNAs Suppress Tumor Progression of Gliomas via Regulating VAV2. Disease markers 15 36426134
2016 Blinded search for varicella zoster virus in giant cell arteritis (GCA)-positive and GCA-negative temporal arteries. Journal of the neurological sciences 14 27084233
2014 Evaluation of a 32-channel versus a 12-channel head coil for high-resolution post-contrast MRI in giant cell arteritis (GCA) at 3T. European journal of radiology 14 25059598
2006 Nongenomic activation of the GC-A enzyme by resveratrol and estradiol downstream from membrane estrogen receptors in human coronary arterial cells. Nutrition, metabolism, and cardiovascular diseases : NMCD 14 17134961
2025 The giant cell arteritis (GCA) ultrasound score (OGUS) at diagnosis and after initial treatment predicts future relapses in GCA patients: results of a multicentre prospective study. Annals of the rheumatic diseases 13 39919971
2011 Role of the closing base pair for d(GCA) hairpin stability: free energy analysis and folding simulations. Nucleic acids research 13 21724608
2008 Association of CT dinucleotide repeat polymorphism in the 5'-flanking region of the guanylyl cyclase (GC)-A gene with essential hypertension in the Japanese. Hypertension research : official journal of the Japanese Society of Hypertension 13 18360023
2006 Chiral discrimination of alpha-amino acids by the DNA triplet GCA. Chemical communications (Cambridge, England) 13 17220981
1990 Structure and expression of tomato mitochondrial genes coding for tRNA(Cys) (GCA), tRNA(Asn) (GUU) and tRNA(Tyr) (GUA): a native tRNA(Cys) gene is present in dicot plants but absent in monocot plants. Current genetics 13 1701109
2022 Treatment of Giant Cell Arteritis (GCA). Journal of clinical medicine 12 35407411
2016 Grancalcin (GCA) modulates Toll-like receptor 9 (TLR9) mediated signaling through its direct interaction with TLR9. European journal of immunology 11 26648480
2010 GREBP, a cGMP-response element-binding protein repressing the transcription of natriuretic peptide receptor 1 (NPR1/GCA). The Journal of biological chemistry 11 20444705
2024 Downregulation of tRF-Cys-GCA-029 by hyperglycemia promotes tumorigenesis and glycolysis of diabetic breast cancer through upregulating PRKCG translation. Breast cancer research : BCR 10 39039568
2008 Regulation of steroidogenesis by atrial natriuretic peptide (ANP) in the rat testis: differential involvement of GC-A and C receptors. Peptides 10 18778744
2020 Serious infections in people with polymyalgia rheumatica (PMR) or giant cell arteritis (GCA): a time-trend national US study. Clinical rheumatology 9 32399772
2024 Does tocilizumab eliminate inflammation in GCA? A cohort study on repeated temporal artery biopsies. RMD open 8 39740930
2021 CD8+ T Cells in GCA and GPA: Bystanders or Active Contributors? Frontiers in immunology 8 33815414
2018 Liposomal prodigiosin and plasmid encoding serial GCA nucleotides reduce inflammation in microglial and astrocyte cells by ATM/ATR signaling. Journal of neuroimmunology 8 30530109
1992 Comparison of a cloned ANF-sensitive guanylate cyclase (GC-A) with particulate guanylate cyclase from adrenal cortex. Naunyn-Schmiedeberg's archives of pharmacology 8 1347156
2020 Risk profiling for a refractory course of giant cell arteritis: The importance of age and body weight: "Risk profiling for GC resistance in GCA". Seminars in arthritis and rheumatism 7 33065420
2003 Non-genomic effects of tamoxifen on the activation of membrane-bound guanylate cyclase GC-A. The Journal of pharmacy and pharmacology 7 14713365
1989 Anchorage-independent growth of RSV-transformed rat (GCA, W 12 and XC) cells. Folia histochemica et cytobiologica 7 2544467
1988 Refinement of the solution structure of the RNA-DNA hybrid 5'-[r(GCA)d(TGC)]2. Combined use of nuclear magnetic resonance and restrained molecular dynamics. FEBS letters 7 2456957
2007 Further identification of Hb G-Coushatta [beta22(B4)Glu-->Ala (GAA-->GCA)] in Thailand by the polymerase chain reaction-single-strand conformation polymorphism technique and by amplification refractory mutation system-polymerase chain reaction. Hemoglobin 6 17365010
2007 Chiral discrimination of alpha-amino acids by the DNA triplet GCA using amino acids as a co-selector. Journal of mass spectrometry : JMS 6 17605145
2024 Phosphorylation-Dependent Regulation of Guanylyl Cyclase (GC)-A and Other Membrane GC Receptors. Endocrine reviews 5 38713083
2022 Case Report: A Novel Non-Reciprocal ALK Fusion: ALK-GCA and EML4-ALK Were Identified in Lung Adenocarcinoma, Which May Respond to Alectinib Adjuvant-Targeted Therapy. Frontiers in oncology 5 35070986
2022 The haplotypes GCA and ACA in ESR1 gene are associated with the susceptibility of recurrent spontaneous abortion (RSA) in Chinese Han: A case-control study and meta-analysis. Medicine 5 35623066
2014 Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides. Clinical and experimental nephrology 5 24845230
2000 Molecular cloning of a regulatory protein for membrane-bound guanylate cyclase GC-A. Biochemical and biophysical research communications 5 11071862
2024 An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer. Cancers 4 38539453
2023 Incidence of biopsy-proven giant cell arteritis (GCA) in South Australia 2014-2020. Frontiers in medicine 4 37153092
2011 Functional significance of an evolutionarily conserved alanine (GCA) resume codon in tmRNA in Escherichia coli. Journal of bacteriology 4 21602351
1991 Histochemical reactivity of the Geodia cydonium agglutinin (GCA) in human tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 4 2005375
2025 An atypical manifestation of Giant cell arteritis (GCA): constitutional symptoms & lingual ulcer in a 78-Year-Old male with negative temporal artery biopsies. BMC rheumatology 3 40369682
2024 The Joint Vasculitis Registry in German-speaking countries (GeVas): subgroup analysis of 195 GCA patients. Clinical and experimental rheumatology 3 38683207
2023 Acute deletion of the central MR/GR steroid receptor correlates with changes in LTP, auditory neural gain, and GC-A cGMP signaling. Frontiers in molecular neuroscience 3 36873102
2023 Tocilizumab Vs Methotrexate in a Cohort of Patients Affected by Active GCA: A Comparative Clinical and Ultrasonographic Study. Biologics : targets & therapy 3 38059132
2023 Effectiveness and safety of a 26-week taper regimen of glucocorticoid in GCA patients: Results from a prospective cohort study. Seminars in arthritis and rheumatism 3 38142617
2021 The U.S. Veterans Health Administration national giant cell arteritis (GCA) database cohort: incident ophthalmic complications in biopsy-negative GCA patients. Clinical rheumatology 3 33417014
2018 Sp1 mediates phorbol ester (PMA)-induced expression of membrane-bound guanylyl cyclase GC-A in human monocytic THP-1 cells. Acta biochimica Polonica 3 29959857
2018 Regularization and grouping -omics data by GCA method: A transcriptomic case. PloS one 3 30383819
2012 Large-vessel GCA or a late presentation of Takayasu's arteritis? BMJ case reports 3 22669872
2024 The Importance of Early Recognition of Rare Ischaemic Complications of GCA to Prevent Permanent Vision Loss. British journal of hospital medicine (London, England : 2005) 2 39347680
2024 Characteristics associated with anterior ischemic optic neuropathy (AION) in giant cell arteritis (GCA). Clinical rheumatology 2 39427049
2023 Case report: GCA like picture-preceding inaugural MOGAD presentation: A patient with a sudden-onset uniocular blindness. Medicine 2 38065923
2023 Utility of online GCA risk models in predicting the result of temporal artery biopsy within a clinical setting: study of diagnostic and screening tests. Canadian journal of ophthalmology. Journal canadien d'ophtalmologie 2 38114060
2018 A Stab in the Dark: A Case Report of an Atypical Presentation of Giant Cell Arteritis (GCA). Geriatrics (Basel, Switzerland) 2 31011074
1993 Alterations in morphology of REF cells induced by growth factors produced by ASV-transformed (GCA) cells. Folia histochemica et cytobiologica 2 8388811
2026 The influence of baseline aortitis on aortic dilation risk in GCA: a multicentre imaging study. Rheumatology (Oxford, England) 1 41365838
2025 Exploring the limit of image resolution for human expert classification of vascular ultrasound images in giant cell arteritis and healthy subjects: the GCA-US-AI project. Annals of the rheumatic diseases 1 40514330
2024 Bing-Neel Syndrome: An Unknown GCA Mimicker. Case reports in rheumatology 1 39161396
2024 Predictive biomarkers of response to tocilizumab in giant cell arteritis (GCA): correlations with imaging activity. Immunologic research 1 39210189
2024 Giant cell arteritis (GCA) as a risk factor for seizures: a cohort study. Postgraduate medicine 1 39365665
2023 Orbital MRI Findings in a Patient With Giant Cell Arteritis (GCA): A Case Report. Cureus 1 38152789
1995 Taq52 I, a novel and thermostable type II restriction endonuclease from the genus Thermus, recognising the pentanucleotide sequence GC(A or T)GC and cleaving DNA between the first and second bases of the recognition sequence: G decreased or reduced C(A or T)GC. Nucleic acids research 1 8524644
2026 m5C-Modified tRF3b-CysGCA-23 Suppresses Bladder Cancer Malignancy by Repressing H3K18 Lactylation via Stabilizing RBM4. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41757512
2025 Case Report: Concurrent Babesiosis and GCA/PMR. Immunity, inflammation and disease 0 40105678
2024 Ultrasound in GCA: Halo Sign Quantification and Visual Symptoms, Systemic Inflammation and Relapse Risk. Mediterranean journal of rheumatology 0 39463873
2024 Genetic Analysis of GCA Repeats in the GLS Gene: Implications for Undiagnosed Ataxia and Spinocerebellar Ataxia 3 in Mainland China. Movement disorders : official journal of the Movement Disorder Society 0 39699045

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