Affinage

C1QL4

Complement C1q-like protein 4 · UniProt Q86Z23

Length
238 aa
Mass
24.9 kDa
Annotated
2026-04-28
11 papers in source corpus 6 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C1QL4 is a secreted complement C1q-domain protein that assembles into homo- and heteromeric complexes via N-terminal cysteine residues and signals through the cell-adhesion GPCR BAI3 to regulate cell fusion, synapse density, angiogenesis, and steroidogenesis (PMID:20525073, PMID:21262840). The globular C1q domain of C1QL4 binds the thrombospondin-repeat domain of BAI3, and this interaction decreases synapse density in cultured neurons and represses BAI3/Elmo/Dock1-dependent myoblast fusion during muscle regeneration (PMID:21262840, PMID:30367035). C1QL4 also activates the c-Raf/MEK1/2/ERK1/2 and cAMP/PKA/CREB signaling cascades to promote endothelial cell migration and tube formation and to stimulate testosterone secretion in Leydig cells, with the ERK and cAMP pathways partially operating through a BAI3-independent receptor (PMID:27734226, PMID:30608882). Constitutive knockout mice are viable with normal muscle and testosterone levels but exhibit sexually dimorphic alterations in energy homeostasis, indicating a modest in vivo role in systemic metabolism (PMID:35579659).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2010 Medium

    Establishing C1QL4 as a secreted, multimeric protein resolved the basic biochemical nature of the gene product and showed it could form heteromeric assemblies with other C1ql family members.

    Evidence Heterologous expression, gel filtration, co-immunoprecipitation, and secretion assays in transfected cells

    PMID:20525073

    Open questions at the time
    • Stoichiometry and precise oligomeric architecture not resolved
    • Native tissue complexes not characterized
    • Single-lab characterization without independent replication
  2. 2011 High

    Identification of BAI3 as the high-affinity receptor for C1QL4 (via the C1q domain–thrombospondin-repeat interaction) provided the first receptor–ligand axis and linked C1QL4 to synapse regulation.

    Evidence Biochemical pulldown/affinity assay, domain-mapping with thrombospondin-repeat fragment competition, neuronal synapse density assay

    PMID:21262840

    Open questions at the time
    • Downstream signaling pathway from BAI3 in neurons not identified
    • In vivo synapse phenotype not examined
  3. 2016 Medium

    Demonstrating that C1QL4 activates the c-Raf/MEK1/2/ERK1/2 cascade to drive endothelial migration and tube formation extended its function beyond the nervous system and identified the first intracellular signaling pathway downstream of C1QL4.

    Evidence Recombinant C1QL4 treatment of HUVECs, tube formation and migration assays, phosphoprotein western blots, MEK inhibitor blockade, chick yolk sac membrane angiogenesis assay

    PMID:27734226

    Open questions at the time
    • Whether BAI3 or another receptor directly transduces the angiogenic signal was not resolved
    • In vivo angiogenesis phenotype in mammals not tested
    • Single-lab study
  4. 2018 High

    Showing that C1QL4 represses BAI3-mediated myoblast fusion via the Elmo/Dock1 pathway in a BAI3 knockout mouse model established that C1QL4 acts as an endogenous antagonist of BAI3 GPCR signaling in muscle.

    Evidence BAI3 knockout mouse, proteomic pulldown, co-immunoprecipitation, GPCR activation assay, cardiotoxin-induced muscle regeneration

    PMID:30367035

    Open questions at the time
    • Whether C1QL4 is the physiologically dominant C1ql ligand of BAI3 in muscle is unclear
    • Structural basis of antagonism versus agonism at BAI3 not resolved
  5. 2019 Medium

    Revealing that C1QL4 stimulates testosterone secretion through dual ERK1/2 and cAMP/PKA/CREB pathways — partly BAI3-dependent and partly BAI3-independent — uncovered a second receptor system and a steroidogenic function.

    Evidence Recombinant C1QL4 treatment of TM3 Leydig cells, Bai3 knockdown, western blot, testosterone ELISA, in situ hybridization

    PMID:30608882

    Open questions at the time
    • Identity of the BAI3-independent receptor remains unknown
    • Single-lab study without independent replication
    • In vivo relevance to testosterone production not confirmed
  6. 2022 Medium

    Constitutive C1QL4 knockout mice showed that in vivo muscle development and testosterone levels are dispensable for C1QL4, while sexually dimorphic metabolic phenotypes revealed a modest role in systemic energy homeostasis.

    Evidence Constitutive knockout mouse with metabolic phenotyping (indirect calorimetry, glucose tolerance, body composition) and muscle function assays

    PMID:35579659

    Open questions at the time
    • Mechanism underlying sexually dimorphic metabolic effects unknown
    • Redundancy with other C1ql family members not tested
    • Single-lab study with modest effect sizes

Open questions

Synthesis pass · forward-looking unresolved questions
  • The identity of the BAI3-independent receptor(s) for C1QL4 and the structural basis of how C1QL4 switches between agonistic and antagonistic modes at BAI3 remain unresolved.
  • No BAI3-independent receptor identified
  • No structural model of C1QL4–BAI3 complex
  • In vivo synapse phenotype of C1QL4 loss not examined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 1
Pathway
R-HSA-1500931 Cell-Cell communication 2 R-HSA-162582 Signal Transduction 2
Partners
BAI3C1QL1C1QL2C1QL3

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 C1QL4 (and other C1ql proteins) bind with high affinity to the extracellular thrombospondin-repeat domain of the cell-adhesion GPCR BAI3, mediated by the globular C1q domain of C1ql proteins; this interaction decreases synapse density in cultured neurons. Biochemical binding assay (pulldown/affinity), domain-mapping with thrombospondin-repeat fragment competition, neuronal synapse density assay Proceedings of the National Academy of Sciences of the United States of America High 21262840
2010 C1QL4 is a secreted protein that forms both homomeric and heteromeric complexes with other C1ql family members, and assembles into hexameric and higher-order complexes via N-terminal cysteine residues. Heterologous cell expression, biochemical characterization (gel filtration, co-immunoprecipitation), secretion assay The European journal of neuroscience Medium 20525073
2018 C1QL4 (and other C1q-like proteins) represses BAI3-mediated myoblast fusion by specifically interacting with BAI3 and antagonizing its GPCR activity; BAI3 signals through Elmo/Dock1 and heterotrimeric G-proteins to promote fusion. Knockout mouse model (BAI3 KO), proteomic approach, co-immunoprecipitation, GPCR activity assay, cardiotoxin-induced muscle regeneration model Nature communications High 30367035
2016 C1QL4 directly stimulates migration and capillary tube formation (angiogenesis) of HUVECs through activation of the c-Raf/MEK1/2/ERK1/2/p90RSK signaling cascade; this effect is blocked by MEK1/2 inhibitor U0126, and BAI3 receptor is detected in HUVECs suggesting BAI3-mediated signaling. Recombinant protein co-culture with HUVECs, tube formation and migration assays, phosphoprotein western blot, MEK inhibitor blockade, chick yolk sac membrane angiogenesis assay Molecular and cellular biochemistry Medium 27734226
2019 C1QL4 promotes testosterone secretion in Leydig cells by increasing StAR protein and steroidogenic enzyme expression via activation of c-Raf/MEK1/2/ERK1/2/MSK1 and cAMP/PKA/CREB signaling cascades; BAI3 mediates part of this effect, but a BAI3-independent receptor also mediates ERK1/2 and cAMP activation by C1QL4. Recombinant C1QL4 treatment of TM3 Leydig cells, Bai3 knockdown, western blot for signaling intermediates and steroidogenic proteins, testosterone ELISA, in situ hybridization for localization FASEB journal Medium 30608882
2022 CTRP11/C1QL4 knockout mice have normal skeletal muscle mass, function, and testosterone levels, but show sexually dimorphic metabolic phenotypes including altered fasting ketones, physical activity, and glucose tolerance, indicating C1QL4 is dispensable for muscle development and testosterone production in vivo but contributes modestly to energy homeostasis. Constitutive knockout mouse, metabolic phenotyping (indirect calorimetry, glucose tolerance test, body composition), muscle function assays FASEB journal Medium 35579659

Source papers

Stage 0 corpus · 11 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. Proceedings of the National Academy of Sciences of the United States of America 149 21262840
2010 Distinct expression of C1q-like family mRNAs in mouse brain and biochemical characterization of their encoded proteins. The European journal of neuroscience 75 20525073
2014 Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients. Gene 74 24582973
2013 C1q/tumor necrosis factor-related protein 11 (CTRP11), a novel adipose stroma-derived regulator of adipogenesis. The Journal of biological chemistry 60 23449976
2018 Spatiotemporal regulation of the GPCR activity of BAI3 by C1qL4 and Stabilin-2 controls myoblast fusion. Nature communications 49 30367035
2016 C1ql1/Ctrp14 and C1ql4/Ctrp11 promote angiogenesis of endothelial cells through activation of ERK1/2 signal pathway. Molecular and cellular biochemistry 25 27734226
2024 Physiological and transcriptomic analysis provides new insights into osmoregulation mechanism of Ruditapes philippinarum under low and high salinity stress. The Science of the total environment 16 38750748
2019 Expression patterns of C1ql4 and its cell-adhesion GPCR Bai3 in the murine testis and functional roles in steroidogenesis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 30608882
2022 CTRP11 contributes modestly to systemic metabolism and energy balance. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 11 35579659
2023 C1ql4 regulates breast cancer cell stemness and epithelial-mesenchymal transition through PI3K/AKT/NF-κB signaling pathway. Frontiers in oncology 3 37324011
2023 Transcriptome Analysis Reveals the Genes Involved in Oxidative Stress Responses of Scallop to PST-Producing Algae and a Candidate Biomarker for PST Monitoring. Antioxidants (Basel, Switzerland) 2 37371880