Details for: C1R

Gene ID: 715

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: C1R

Ensembl ID: ENSG00000159403

Description: complement C1r

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • bronchus fibroblast of lung CL2000093
    CSI 41.07
    rCSI 33.37%
    PRS 93.12
  • fibroblast of lung CL0002553
    CSI 36.24
    rCSI 33.72%
    PRS 94.77
  • skin fibroblast CL0002620
    CSI 28.67
    rCSI 24.71%
    PRS 93.07
  • alveolar adventitial fibroblast CL4028006
    CSI 26.23
    rCSI 41.43%
    PRS 94.5
  • adipocyte CL0000136
    CSI 25.03
    rCSI 32.14%
    PRS 86.81
  • hepatocyte CL0000182
    CSI 23.72
    rCSI 42.45%
    PRS 91.99
  • keratocyte CL0002363
    CSI 23.35
    rCSI 56.13%
    PRS 94.12
  • adventitial cell CL0002503
    CSI 21.76
    rCSI 51.96%
    PRS 95.39
  • alveolar type 1 fibroblast cell CL4028004
    CSI 18.15
    rCSI 19.88%
    PRS 94.87
  • stromal cell of ovary CL0002132
    CSI 17.07
    rCSI 46.91%
    PRS 95.65
  • vascular associated smooth muscle cell CL0000359
    CSI 15.02
    rCSI 48.71%
    PRS 92.22
  • myofibroblast cell CL0000186
    CSI 13.65
    rCSI 18.9%
    PRS 90.97
  • centrilobular region hepatocyte CL0019029
    CSI 13.5
    rCSI 35.23%
    PRS 89.77
  • microcirculation associated smooth muscle cell CL0008035
    CSI 13.4
    rCSI 38.8%
    PRS 92.93
  • stromal cell CL0000499
    CSI 13.39
    rCSI 37.68%
    PRS 90.44
  • pulmonary artery endothelial cell CL1001568
    CSI 12.67
    rCSI 17.24%
    PRS 96.55
  • respiratory basal cell CL0002633
    CSI 11.92
    rCSI 12.35%
    PRS 94.77
  • perivascular cell CL4033054
    CSI 11.88
    rCSI 16.24%
    PRS 95.95
  • epithelial cell of lower respiratory tract CL0002632
    CSI 10.79
    rCSI 8.36%
    PRS 95.36
  • hepatic stellate cell CL0000632
    CSI 10.71
    rCSI 40.13%
    PRS 90.64
  • fibroblast of breast CL4006000
    CSI 9.9
    rCSI 41.64%
    PRS 95.25
  • midzonal region hepatocyte CL0019028
    CSI 9.38
    rCSI 22.01%
    PRS 90.69
  • Schwann cell CL0002573
    CSI 8.72
    rCSI 24.78%
    PRS 90.71
  • blood vessel endothelial cell CL0000071
    CSI 8.47
    rCSI 17.57%
    PRS 92.24
  • fibroblast CL0000057
    CSI 8.43
    rCSI 24.26%
    PRS 84.55
  • mesenchymal stem cell of adipose tissue CL0002570
    CSI 8.34
    rCSI 46.51%
    PRS 94.47
  • smooth muscle cell CL0000192
    CSI 8.12
    rCSI 19.37%
    PRS 88.51
  • Kupffer cell CL0000091
    CSI 7.31
    rCSI 16.72%
    PRS 94.47
  • mononuclear phagocyte CL0000113
    CSI 7.09
    rCSI 15.61%
    PRS 95.64
  • fallopian tube secretory epithelial cell CL4030006
    CSI 7.06
    rCSI 6.79%
    PRS 92.42
  • interstitial cell of Cajal CL0002088
    CSI 7.05
    rCSI 8.98%
    PRS 95.94
  • periportal region hepatocyte CL0019026
    CSI 6.89
    rCSI 26.81%
    PRS 90.42
  • intrahepatic cholangiocyte CL0002538
    CSI 6.86
    rCSI 16.47%
    PRS 93.26
  • lung pericyte CL0009089
    CSI 6.82
    rCSI 18%
    PRS 96.37
  • tracheobronchial smooth muscle cell CL0019019
    CSI 6.6
    rCSI 11.64%
    PRS 95.57
  • epithelial cell of lung CL0000082
    CSI 6.22
    rCSI 5.16%
    PRS 94.55
  • kidney interstitial fibroblast CL1000692
    CSI 5.92
    rCSI 31.44%
    PRS 87.93
  • stratified epithelial cell CL0000079
    CSI 5.87
    rCSI 36.21%
    PRS 95.11
  • pancreatic acinar cell CL0002064
    CSI 5.8
    rCSI 7.71%
    PRS 95.56
  • retinal blood vessel endothelial cell CL0002585
    CSI 5.73
    rCSI 9.16%
    PRS 95.33
  • keratinocyte CL0000312
    CSI 5.73
    rCSI 4.8%
    PRS 93.27
  • basal cell CL0000646
    CSI 5.63
    rCSI 7.52%
    PRS 91.11
  • respiratory suprabasal cell CL4033048
    CSI 5.53
    rCSI 7.09%
    PRS 94.62
  • chondrocyte CL0000138
    CSI 4.74
    rCSI 7.53%
    PRS 90.05
  • pancreatic stellate cell CL0002410
    CSI 4.73
    rCSI 27.54%
    PRS 94.71
  • enteric smooth muscle cell CL0002504
    CSI 4.65
    rCSI 6.64%
    PRS 93.43
  • myoepithelial cell CL0000185
    CSI 4.59
    rCSI 11.6%
    PRS 95.08
  • mesodermal cell CL0000222
    CSI 4.54
    rCSI 5.45%
    PRS 92.73
  • contractile cell CL0000183
    CSI 4.44
    rCSI 13.11%
    PRS 93.28
  • fibroblast of cardiac tissue CL0002548
    CSI 4.15
    rCSI 19.9%
    PRS 94.4
  • respiratory hillock cell CL4030023
    CSI 4.13
    rCSI 7.36%
    PRS 95.94
  • lung endothelial cell CL1001567
    CSI 4.06
    rCSI 9.46%
    PRS 97.44
  • smooth muscle cell of prostate CL1000487
    CSI 3.78
    rCSI 22.22%
    PRS 95.85
  • myeloid leukocyte CL0000766
    CSI 3.3
    rCSI 3.05%
    PRS 94.77
  • conjunctival epithelial cell CL1000432
    CSI 3.11
    rCSI 4.76%
    PRS 92.69
  • pancreatic ductal cell CL0002079
    CSI 3.03
    rCSI 5.9%
    PRS 94.57
  • bronchiolar smooth muscle cell CL4033017
    CSI 2.76
    rCSI 41.41%
    PRS 96.49
  • mesenchymal cell CL0008019
    CSI 2.7
    rCSI 6.86%
    PRS 89.77
  • basal cell of prostate epithelium CL0002341
    CSI 2.51
    rCSI 7.25%
    PRS 95.11
  • blood vessel smooth muscle cell CL0019018
    CSI 2.5
    rCSI 20.35%
    PRS 92.21
  • exhausted T cell CL0011025
    CSI 2.35
    rCSI 39.81%
    PRS 95.63
  • tendon cell CL0000388
    CSI 2.35
    rCSI 6.1%
    PRS 94.99
  • uterine smooth muscle cell CL0002601
    CSI 2.07
    rCSI 13.64%
    PRS 95.59
  • renal interstitial pericyte CL1001318
    CSI 2.03
    rCSI 5.59%
    PRS 91.91
  • mesenchymal stem cell CL0000134
    CSI 2
    rCSI 21.95%
    PRS 94.8
  • endothelial cell of pericentral hepatic sinusoid CL0019022
    CSI 1.96
    rCSI 6.05%
    PRS 94.63
  • smooth muscle cell of the pulmonary artery CL0002591
    CSI 1.66
    rCSI 12.72%
    PRS 94.2
  • epicardial adipocyte CL1000309
    CSI 1.52
    rCSI 4.94%
    PRS 91.27
  • endothelial cell of uterus CL0009095
    CSI 1.44
    rCSI 10.54%
    PRS 96.84
  • mesenchymal lymphangioblast CL0005021
    CSI 1.19
    rCSI 31.35%
    PRS 96.18
  • parietal epithelial cell CL1000452
    CSI 0.98
    rCSI 2.61%
    PRS 89.89
  • kidney interstitial cell CL1000500
    CSI 0.62
    rCSI 10.11%
    PRS 95.11

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [C1R](/details-gene/715) (Complement C1r) is a protein-coding gene that encodes a subcomponent of the C1 complex, the first component of the classical pathway of the complement system. Functioning as a serine protease, [C1R](/details-gene/715) is essential for the autoactivation of the C1 complex upon binding to antigen-antibody complexes, thereby initiating the complement cascade. While classically known as a circulating protein primarily synthesized by the liver, expression data indicates significant local production in various mesenchymal cell types, including [bronchus fibroblast of lung](/details-cell/CL2000093), [fibroblast of lung](/details-cell/CL0002553), and [adipocyte](/details-cell/CL0000136). Clinically, mutations in [C1R](/details-gene/715) are associated with Periodontal Ehlers-Danlos Syndrome ([130080](https://omim.org/entry/130080)), highlighting a role beyond canonical immunity in connective tissue homeostasis. ## Cellular Roles and Expression Landscape The expression profile of [C1R](/details-gene/715) reveals a prominent role in stromal and parenchymal cell biology. **Overall**, the gene shows the highest significance in cells of mesenchymal origin. It is a top marker for multiple fibroblast populations, including [bronchus fibroblast of lung](/details-cell/CL2000093) (CSI: 41.07), [fibroblast of lung](/details-cell/CL0002553) (CSI: 36.24), [skin fibroblast](/details-cell/CL0002620) (CSI: 28.67), and various specialized lung fibroblasts. This widespread expression in fibroblasts across different tissues suggests that local, tissue-specific synthesis of C1R is a key feature of innate immune surveillance and tissue homeostasis. Beyond fibroblasts, [C1R](/details-gene/715) is also highly significant in [adipocyte](/details-cell/CL0000136)s (CSI: 25.03) and [hepatocyte](/details-cell/CL0000182)s (CSI: 23.72), which is consistent with the liver's role as the primary source of circulating complement proteins and points to a potential role for adipocyte-derived complement in metabolic inflammation. Furthermore, significant expression in [vascular associated smooth muscle cell](/details-cell/CL0000359) and other [stromal cell](/details-cell/CL0000499) types underscores its broad importance in maintaining the structural and immunological integrity of tissues. The data collectively suggest that while hepatocytes produce [C1R](/details-gene/715) for systemic circulation, a distributed network of stromal cells provides an immediate, localized source of this critical complement component. ## Pathways and Molecular Function Functionally, [C1R](/details-gene/715) is a cornerstone of the innate immune system. Its molecular function is dominated by its [serine-type endopeptidase activity](/content/detail/GO:0004252) ([GO:0004252](https://www.ebi.ac.uk/QuickGO/term/GO:0004252)), which is activated following a conformational change in the C1 complex. This enzymatic activity is central to the biological process of [complement activation, classical pathway](/content/detail/GO:0006958) ([GO:0006958](https://www.ebi.ac.uk/QuickGO/term/GO:0006958)), as detailed in the Reactome pathway [Classical antibody-mediated complement activation](/content/detail/R-HSA-173623) ([R-HSA-173623](https://reactome.org/content/detail/R-HSA-173623)). The protein itself is part of a larger molecular assembly and exhibits [calcium ion binding](/content/detail/GO:0005509) ([GO:0005509](https://www.ebi.ac.uk/QuickGO/term/GO:0005509)) and [identical protein binding](/content/detail/GO:0042802) ([GO:0042802](https://www.ebi.ac.uk/QuickGO/term/GO:0042802)) capabilities, which are critical for the structural integrity and autoactivation of the C1q-C1r2-C1s2 complex. As an extracellular protein found in the [extracellular space](/content/detail/GO:0005615) ([GO:0005615](https://www.ebi.ac.uk/QuickGO/term/GO:0005615)) and associated with [blood microparticle](/content/detail/GO:0072562)s ([GO:0072562](https://www.ebi.ac.uk/QuickGO/term/GO:0072562)), its function is integral to the broader [immune system](/content/detail/R-HSA-168256) ([R-HSA-168256](https://reactome.org/content/detail/R-HSA-168256)). ## Research Directions The association of [C1R](/details-gene/715) mutations with Periodontal Ehlers-Danlos Syndrome, a connective tissue disorder, points to functions beyond classical pathogen clearance [Link](https://doi.org/10.1016/j.ajhg.2016.08.019). This, combined with its high expression in various fibroblast populations, suggests a potential role in extracellular matrix (ECM) dynamics and tissue repair. **Testable Hypotheses:** 1. Fibroblast-secreted [C1R](/details-gene/715) directly modulates ECM integrity by cleaving specific matrix components or by regulating the activity of matrix metalloproteinases (MMPs), and its deficiency leads to the connective tissue fragility observed in Periodontal Ehlers-Danlos Syndrome. 2. [C1R](/details-gene/715) produced by adipocytes contributes to low-grade chronic inflammation ("meta-inflammation") in adipose tissue by initiating local complement activation in response to metabolic stress, thereby linking complement to the pathogenesis of obesity-related metabolic disorders. **Proposed Experiment:** To test the first hypothesis regarding the role of [C1R](/details-gene/715) in ECM modulation, one could utilize an *in vitro* model of human dermal fibroblasts. Expression of [C1R](/details-gene/715) could be knocked down using shRNA or CRISPRi. The resulting cell cultures and their conditioned media would be analyzed for changes in ECM composition (e.g., collagen I, fibronectin levels via western blot) and turnover. A proteomics-based substrate screen (e.g., PICS) could be performed using recombinant C1r protease to identify novel, non-canonical substrates within the ECM, potentially revealing a direct link between its enzymatic activity and matrix remodeling. **Therapeutic Potential:** As a key initiating protease in the classical complement pathway, [C1R](/details-gene/715) is a compelling target for **inhibition** in diseases driven by antibody-mediated complement activation, such as certain autoimmune disorders (e.g., lupus nephritis) and antibody-mediated transplant rejection. Its serine protease activity makes it a druggable target for small molecule inhibitors. However, its widespread expression in structural cells like fibroblasts and its genetic link to a connective tissue disorder suggest that systemic, complete inhibition could have significant adverse effects on tissue homeostasis. Therefore, therapeutic strategies might require targeted delivery to specific tissues or the development of inhibitors that finely modulate, rather than ablate, its activity.

Genular Protein ID: 642947284

Symbol: C1R_HUMAN

Name: Complement C1r subcomponent

UniProtKB Accession Codes:

P00736 A6NJQ8 Q68D77 Q8J012

Database IDs:

AGR 1 AlphaFoldDB 1 BRENDA 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 4 CTD 1 ChEMBL 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 9 DrugCentral 1 EC 2 EMBL 7 EvolutionaryTrace 1 GO 13 Gene3D 4 GeneCards 1 GeneReviews 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 InParanoid 1 IntAct 1 InterPro 13 KEGG 1 MEROPS 1 MIM 4 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 9 PDBsum 9 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 7 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 4 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 3 RefSeq 1 SABIO-RK 1 SASBDB 1 SIGNOR 1 SMART 5 SMR 1 STRING 1 SUPFAM 4 SignaLink 1 TreeFam 1 UCSC 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 3021205

Title: Nucleotide sequence of the cDNA coding for human complement C1r.

PubMed ID: 3021205

DOI: 10.1021/bi00365a020

PubMed ID: 3030286

Title: Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r.

PubMed ID: 3030286

DOI: 10.1042/bj2400783

PubMed ID: 12914573

Title: The human complement component C1R gene: the exon-intron structure and the molecular basis of allelic diversity.

PubMed ID: 12914573

DOI: 10.1046/j.1469-1809.2003.00019.x

PubMed ID: 17974005

Title: The full-ORF clone resource of the German cDNA consortium.

PubMed ID: 17974005

DOI: 10.1186/1471-2164-8-399

PubMed ID: 16541075

Title: The finished DNA sequence of human chromosome 12.

PubMed ID: 16541075

DOI: 10.1038/nature04569

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 3036070

Title: Complete amino acid sequence of the A chain of human complement-classical-pathway enzyme C1r.

PubMed ID: 3036070

DOI: 10.1042/bj2410711

PubMed ID: 6303394

Title: Complete amino acid sequence of the catalytic chain of human complement subcomponent C1-r.

PubMed ID: 6303394

DOI: 10.1021/bi00277a003

PubMed ID: 2820791

Title: Identification of erythro-beta-hydroxyasparagine in the EGF-like domain of human C1r.

PubMed ID: 2820791

DOI: 10.1016/0014-5793(87)80205-3

PubMed ID: 8635594

Title: Identification of a cryptic protein kinase CK2 phosphorylation site in human complement protease Clr, and its use to probe intramolecular interaction.

PubMed ID: 8635594

DOI: 10.1016/0014-5793(96)00403-6

PubMed ID: 2831944

Title: Complete cDNA sequence of human complement Cls and close physical linkage of the homologous genes Cls and Clr.

PubMed ID: 2831944

DOI: 10.1021/bi00400a004

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 27745832

Title: Periodontal Ehlers-Danlos syndrome is caused by mutations in C1R and C1S, which encode subcomponents C1r and C1s of complement.

PubMed ID: 27745832

DOI: 10.1016/j.ajhg.2016.08.019

PubMed ID: 9477945

Title: Solution structure of the epidermal growth factor (EGF)-like module of human complement protease C1r, an atypical member of the EGF family.

PubMed ID: 9477945

DOI: 10.1021/bi971851v

PubMed ID: 11823416

Title: The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex.

PubMed ID: 11823416

DOI: 10.1093/emboj/21.3.231

PubMed ID: 12429092

Title: Monomeric structures of the zymogen and active catalytic domain of complement protease c1r: further insights into the c1 activation mechanism.

PubMed ID: 12429092

DOI: 10.1016/s0969-2126(02)00881-x

PubMed ID: 8162045

Title: A common amino acid polymorphism in complement component C1R.

PubMed ID: 8162045

DOI: 10.1093/hmg/3.1.217-a

PubMed ID: 22028381

Title: Quantitative detection of single amino acid polymorphisms by targeted proteomics.

PubMed ID: 22028381

DOI: 10.1093/jmcb/mjr024

Sequence Information:

  • Length: 705
  • Mass: 80119
  • Checksum: B45D120201061462
  • Sequence:
    • MWLLYLLVPA LFCRAGGSIP IPQKLFGEVT SPLFPKPYPN NFETTTVITV PTGYRVKLVF 
QQFDLEPSEG CFYDYVKISA DKKSLGRFCG QLGSPLGNPP GKKEFMSQGN KMLLTFHTDF 
SNEENGTIMF YKGFLAYYQA VDLDECASRS KSGEEDPQPQ CQHLCHNYVG GYFCSCRPGY 
ELQEDTHSCQ AECSSELYTE ASGYISSLEY PRSYPPDLRC NYSIRVERGL TLHLKFLEPF 
DIDDHQQVHC PYDQLQIYAN GKNIGEFCGK QRPPDLDTSS NAVDLLFFTD ESGDSRGWKL 
RYTTEIIKCP QPKTLDEFTI IQNLQPQYQF RDYFIATCKQ GYQLIEGNQV LHSFTAVCQD 
DGTWHRAMPR CKIKDCGQPR NLPNGDFRYT TTMGVNTYKA RIQYYCHEPY YKMQTRAGSR 
ESEQGVYTCT AQGIWKNEQK GEKIPRCLPV CGKPVNPVEQ RQRIIGGQKA KMGNFPWQVF 
TNIHGRGGGA LLGDRWILTA AHTLYPKEHE AQSNASLDVF LGHTNVEELM KLGNHPIRRV 
SVHPDYRQDE SYNFEGDIAL LELENSVTLG PNLLPICLPD NDTFYDLGLM GYVSGFGVME 
EKIAHDLRFV RLPVANPQAC ENWLRGKNRM DVFSQNMFCA GHPSLKQDAC QGDSGGVFAV 
RDPNTDRWVA TGIVSWGIGC SRGYGFYTKV LNYVDWIKKE MEEED