Affinage

C4A

Complement C4-A · UniProt P0C0L4

Round 2 corrected
Length
1744 aa
Mass
192.8 kDa
Annotated
2026-04-28
130 papers in source corpus 21 papers cited in narrative 21 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C4A is a classical complement pathway component that, upon C1s-mediated cleavage of its alpha-chain, generates C4a anaphylatoxin and nascent C4b, which covalently deposits on immune complexes preferentially via amide bonds to amino groups, conferring superior opsonization of protein antigens and enhanced CR1-mediated clearance compared with the C4B isotype (PMID:6332733, PMID:2138067). This isotype specificity maps to four amino acid differences in the C4d region (positions 1101–1106) (PMID:2431902), and the deposited C4b assembles with C2 to form the classical pathway C3 convertase (PMID:6019133). Beyond its role in humoral immunity—where macrophage-derived C4 is sufficient to support germinal center responses in the absence of serum C4 (PMID:12421924)—C4A is expressed in the brain by astrocytes and localizes to neuronal synapses, where it mediates complement-dependent synaptic pruning by microglia; higher C4A expression increases schizophrenia risk while protecting against SLE and Sjögren's syndrome in a sex-dependent manner correlated with sex differences in complement protein levels (PMID:26814963, PMID:32499649).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1967 High

    Establishing that C4 interacts with C2 and, after C1 esterase cleavage, forms a stable C3 convertase defined the enzymatic core of the classical complement pathway and positioned C4 as an essential upstream component.

    Evidence Purified component reconstitution with functional hemolysis assay

    PMID:6019133

    Open questions at the time
    • C4A vs C4B isotype distinction not yet known
    • covalent binding mechanism of nascent C4b not characterized
  2. 1972 Medium

    Demonstrating that somatic hybrid cells autonomously synthesize functional C4 established that C4 is encoded by a nuclear gene and can be produced cell-autonomously outside the liver.

    Evidence HeLa–guinea-pig macrophage somatic cell fusion with hemolytic complement assay

    PMID:5033180

    Open questions at the time
    • identity of the human chromosomal locus unknown
    • tissue-specific regulation not addressed
  3. 1981 High

    Sequencing C4a anaphylatoxin revealed its generation by C1s cleavage at position 77–78 of the alpha-chain and established C3a/C4a/C5a as a structurally related anaphylatoxin family, raising the question of C4a-specific receptor signaling.

    Evidence Protein isolation, cyanogen bromide fragmentation, and direct amino acid sequencing from human serum C4

    PMID:6167582

    Open questions at the time
    • C4a receptor identity unknown
    • biological activity of C4a not yet defined
  4. 1984 High

    Full cDNA sequencing of C4A defined the 1722-residue precursor and, together with biochemical studies, revealed that C4A and C4B differ in covalent binding chemistry—C4A preferentially forms amide bonds with amino groups on protein antigens while C4B preferentially forms ester bonds—explaining their distinct functional niches in immune complex handling versus cell-surface hemolysis.

    Evidence cDNA cloning from liver mRNA; purified isotype binding assays on antibody-coated red cells and protein-antigen complexes; hemolytic titration and radiolabeled deposition

    PMID:6332733 PMID:6546706 PMID:6609966

    Open questions at the time
    • specific residues responsible for binding chemistry difference not yet identified
    • in vivo consequences of C4A deficiency not established
  5. 1984 High

    Genomic mapping placed C4A and C4B ~10 kb apart within a 98 kb segment of the MHC class III region on chromosome 6, establishing the tandem duplication architecture and linking complement variation to MHC haplotype diversity.

    Evidence Overlapping cosmid clones and restriction mapping of genomic DNA

    PMID:6559257

    Open questions at the time
    • copy number variation at the locus not yet appreciated
    • regulatory elements controlling isotype-specific expression unknown
  6. 1988 High

    Mapping Rodgers/Chido blood group determinants to C4A/C4B and pinpointing four isotypic residues in C4d (1101–1106) as the molecular basis of both antigenic and chemical-reactivity differences resolved how minimal sequence changes drive functional isotype divergence.

    Evidence Haemagglutination inhibition with polyspecific antisera; nucleotide sequencing of C4d region allotypes; fluid-phase covalent binding assays with purified C4A3 and C4B1

    PMID:2431902 PMID:2483343 PMID:3264881

    Open questions at the time
    • structural basis of how these four residues alter thioester reactivity not resolved
    • rare variant allotypes can dissociate serological and chemical phenotypes
  7. 1988 Medium

    Characterizing tissue-specific C4 mRNA expression in mouse revealed broad expression beyond the liver—including brain, lung, kidney, and macrophages—suggesting local complement production may serve tissue-specific immune functions.

    Evidence Northern blotting across multiple mouse tissues with congenic strain controls

    PMID:3405752

    Open questions at the time
    • human tissue expression pattern not directly addressed
    • functional significance of extrahepatic C4 production unknown
  8. 1990 High

    Demonstrating that C4A-opsonized immune complexes bind CR1 on erythrocytes far more effectively than C4B-opsonized complexes established that C4A's functional superiority in immune complex clearance operates at the level of receptor engagement, not just covalent deposition.

    Evidence CR1 binding assay and immunoprecipitation inhibition with purified C4A and C4B on preformed and nascent immune complexes

    PMID:2138067

    Open questions at the time
    • structural explanation for differential CR1 engagement not provided
    • in vivo clearance studies not performed
  9. 1993 Medium

    Identifying that C4a induces Ca²⁺ mobilization via a receptor distinct from the C3a receptor and inhibits C3a-induced superoxide generation established C4a as a functional anaphylatoxin with immunomodulatory rather than purely pro-inflammatory activity.

    Evidence Intracellular Ca²⁺ measurement, [¹²⁵I]-C3a radioligand competition, and superoxide assay in guinea-pig macrophages

    PMID:8396560

    Open questions at the time
    • molecular identity of the C4a receptor not established
    • relevance to human macrophages not shown
    • downstream signaling pathway not mapped
  10. 1998 Medium

    Showing that human astrocytes constitutively produce C4 and that its expression is regulated by IFN-γ and IL-1β identified a CNS cellular source for locally produced complement, presaging a role for C4 in brain-specific processes.

    Evidence RT-PCR, ELISA, immunocytochemistry, and immunoblot in primary human astrocytes with cytokine treatment

    PMID:9795119

    Open questions at the time
    • C4A vs C4B isotype distinction in astrocyte expression not addressed
    • functional consequence of astrocyte-derived C4 in brain unknown
  11. 2001 Medium

    Identifying GPR77/C5L2 as a receptor that binds C4a (cross-competing with C3a) provided a candidate molecular receptor for C4a signaling, partially resolving the receptor identity question raised by the 1993 guinea-pig macrophage studies.

    Evidence Radioligand cross-competition binding in C5L2-transfected RBL-2H3 cells

    PMID:11773063

    Open questions at the time
    • C5L2 functional signaling in response to C4a not demonstrated
    • physiological relevance of C4a–C5L2 interaction in vivo unknown
  12. 2002 High

    Demonstrating that bone marrow-derived macrophage C4 is sufficient to restore germinal center function and humoral immunity in C4-knockout mice proved that locally produced (non-hepatic) C4 has a non-redundant role in adaptive immunity independent of circulating serum C4.

    Evidence Bone marrow reconstitution of C4⁻/⁻ mice; immunization; in situ hybridization, immunofluorescence, and antibody titer quantification

    PMID:12421924

    Open questions at the time
    • relative contribution of C4A vs C4B isotype in germinal center function not dissected
    • mechanism of C4 action in follicular dendritic cell retention not elucidated
  13. 2016 High

    The landmark discovery that C4A protein localizes to neuronal synapses and mediates complement-dependent synaptic pruning by microglia—with higher C4A expression proportionally increasing schizophrenia risk—established a direct mechanistic link between a complement gene and a psychiatric disorder through a neurodevelopmental pathway.

    Evidence Allele-specific RNA-seq in human brain; C4 immunohistochemistry; C4-knockout and C4-overexpressing mouse models with synapse quantification; population genetic association

    PMID:26814963

    Open questions at the time
    • whether C4A acts via the same C3-dependent tagging pathway in brain as in periphery not fully established
    • cell-type-specific C4A expression regulation in brain not characterized
    • therapeutic modulation of C4A-dependent pruning not demonstrated
  14. 2020 High

    Quantifying sex-differential C4 protein levels and demonstrating that C4A allele dosage generates up to 14–31-fold variation in autoimmune disease risk (SLE, Sjögren's syndrome) while simultaneously increasing schizophrenia risk unified the opposing disease associations into a single framework of complement-mediated self-tolerance versus synaptic pruning, modulated by sex.

    Evidence Large-scale population genetic association with structural C4 genotyping; CSF and plasma C4/C3 protein measurement stratified by sex

    PMID:32499649

    Open questions at the time
    • molecular mechanism by which sex hormones regulate C4 protein levels unknown
    • whether C4A's protective effect in autoimmunity is purely via immune complex clearance or also involves tolerance mechanisms not resolved
  15. 2021 Medium

    In vivo neuroimaging evidence that genetically predicted higher C4A expression correlates with increased microglial activation (TSPO-PET) and altered hippocampal morphology translated the mouse pruning phenotype to living human brain, strengthening the causal model.

    Evidence [¹⁸F]FEPPA TSPO-PET and MRI hippocampal morphometry in 111 participants with C4 structural genotyping

    PMID:34456009

    Open questions at the time
    • TSPO-PET is an indirect marker; direct measurement of synaptic density change not performed
    • sample size moderate; replication in larger cohorts needed
    • causal directionality relies on genetic instrument assumptions

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis by which four C4d residues alter thioester reactivity, the definitive identity and signaling pathway of the C4a receptor in humans, the cell-type-specific regulatory mechanisms controlling C4A expression in the brain, and whether therapeutic modulation of C4A-mediated pruning can alter schizophrenia-related phenotypes.
  • no crystal structure of C4A vs C4B thioester domain to explain differential reactivity
  • C4a receptor signaling pathway in human cells remains unresolved
  • no interventional studies targeting C4A-dependent pruning in disease models

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 5 GO:0098772 molecular function regulator activity 1
Localization
GO:0005576 extracellular region 7 GO:0005829 cytosol 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-112316 Neuronal System 2 R-HSA-1643685 Disease 2 R-HSA-1266738 Developmental Biology 1
Partners
C1SC2C5L2CR1
Complex memberships
C3 convertase (C4b2a)

Evidence

Reading pass · 21 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1967 C4 and C2 interact in free solution to form a reversible protein-protein complex; upon cleavage by C1 esterase in the presence of Mg2+, this complex becomes a stable, enzymatically active C3 convertase that fragments C3, establishing the functional unit of the classical complement pathway. Purified component reconstitution, functional hemolysis assay, molecular weight determination The Journal of experimental medicine High 6019133
1981 Human C4a anaphylatoxin (77 residues, ~9 kDa) is generated by C1s-mediated cleavage of the C4 alpha-chain between positions 77 and 78; primary sequence analysis revealed ~30% homology with C3a and ~36% with C5a, establishing C3a/C4a/C5a as a structurally related family despite immunological distinctiveness. Protein isolation from serum, cyanogen bromide fragmentation, chymotryptic digestion, sequence analysis The Journal of biological chemistry High 6167582
1984 The complete amino acid sequence (1722 residues) of the C4A single-chain precursor was deduced from cDNA cloning; comparison with C4B cDNA sequences identified class-specific nucleotide differences that explain the two isotypes, and allelic differences within C4A. cDNA cloning and nucleotide sequencing from heterozygous donor liver mRNA Cell High 6546706
1984 C4A and C4B differ functionally in their covalent binding chemistry: C4B binds twice as effectively to antibody-coated red cells (hydroxyl-group targets) while C4A binds more effectively to protein-antigen complexes (amino-group targets); C4A preferentially transacylates amino nucleophiles and C4B preferentially acylates hydroxyl groups, despite only small differences in amino acid sequence. Purified C4A and C4B binding assays on antibody-coated red cells and protein-antigen complexes, comparison across a range of concentrations The EMBO journal High 6332733
1984 The molecular basis for C4B's ~4-fold greater immune hemolysis activity versus C4A was traced to greater deposition efficiency of nascent C4b onto C1-bearing erythrocyte surfaces, not to differences in C1s cleavage rate or C3 convertase kinetics; C4A nascent C4b preferentially forms amide bonds while C4B preferentially forms ester bonds with surface acceptors. Purified C4A and C4B from isotype-pure donors; hemolytic titration, C1s cleavage rate assay, C3 convertase decay assay, factor I cleavage assay, radiolabeled deposition quantification on sheep erythrocytes Journal of immunology High 6609966
1984 The C4A and C4B loci were mapped ~30 kb from the C2/factor B genes within a 98 kb segment of chromosome 6 MHC class III region, with the two C4 genes separated from each other by ~10 kb, establishing the genomic organization of the complement gene cluster. Overlapping cosmid clones from genomic DNA library, restriction mapping Nature High 6559257
1984 The C4A/C4B class specificity (chemical reactivity and Rodgers/Chido antigenicity) maps to only four isotypic amino acid differences in the C4d region (positions 1101–1106): C4A carries PCPVLD and C4B carries LSPVIH; gene size polymorphism (22 kb vs 16 kb) was also identified for different allotypes. Cloning of C4A and C4B allotype genes, derived amino acid sequence comparison, restriction mapping The EMBO journal High 2431902
1985 Human C4 glycosylation was characterized: the alpha-chain carries three complex fucosylated biantennary oligosaccharides (on alpha2, alpha3, and alpha4 fragments) and the beta-chain has a single high-mannose oligosaccharide; the ~2000 Da mass difference between C4A and C4B alpha-chains localizes to the alpha2 fragment and is not due to carbohydrate differences. Glycan analysis of purified plasma C4 and HepG2-secreted C4 using lectin and chemical methods; subunit fractionation Journal of immunology High 2981921
1988 Rodgers and Chido blood group antigens map to C4A and C4B respectively; four polymorphic sites in the C4d region correlate with antigen expression, defining conformational or sequential epitopes; the serological phenotype can be dissociated from chemical reactivity class in rare variant allotypes. Haemagglutination inhibition assays with polyspecific antisera; nucleotide sequencing of C4d region from allotypes of known antigenic status Experimental and clinical immunogenetics High 2483343
1988 C4A3 binds immunoglobulins (IgG, IgM, IgA, IgG2a, F(ab')2) and BSA 3–4 times more efficiently than C4B1 in fluid-phase reactions; C4A3 forms predominantly amide linkages with IgG whereas C4B1 forms both amide and ester linkages, mirroring binding preferences observed in solid-phase assays. Fluid-phase covalent binding assay with purified C4A3 and C4B1, C1s, and various immunoglobulin substrates; bond-type determination Molecular immunology High 3264881
1990 The major functional difference between C4A and C4B in immune complex handling is at the level of CR1 (complement receptor 1) binding: C4A-opsonized complexes bind CR1 on erythrocytes markedly more effectively than C4B-opsonized complexes, with C4A also modestly superior at inhibiting immunoprecipitation, particularly in antibody excess. Purified C4A and C4B; immunoprecipitation inhibition assay; CR1 binding assay with preformed and nascent immune complexes on red cells Clinical and experimental immunology High 2138067
1990 Comparative analysis of C4 purified from diverse mammalian species showed that C4B-like (hydroxyl-preferring) binding specificity is the ancestral form; C4A-like (amino-preferring) specificity co-occurs with C4B-like in primates, sheep, and cattle (suggesting independent duplications), while rodents and most other species have only C4B-like activity. C4 purification from multiple species, binding specificity assays The Biochemical journal Medium 2302180
1972 C4-deficient guinea pig peritoneal exudate cells fused with HeLa cells produced functionally active human C4, demonstrating that C4 is encoded by a nuclear gene and can be synthesized by somatic hybrid cells, establishing cell-autonomous C4 biosynthesis. Cell fusion (somatic hybridization), functional complement hemolysis assay Science Medium 5033180
1993 C4a anaphylatoxin induced biphasic Ca2+ mobilization in guinea-pig macrophages (rapid intracellular pool release followed by weak extracellular influx) via a receptor distinct from the C3a receptor (C4a did not compete with [125I]-C3a binding and C4a-desensitized cells still responded to C3a); C4a inhibited C3a-induced superoxide (O2-) generation without itself triggering O2- production. Intracellular Ca2+ measurement, radioligand competition binding ([125I]-C3a), superoxide generation assay in guinea-pig macrophages Immunology letters Medium 8396560
2001 The orphan receptor C5L2/GPR77 binds C4a anaphylatoxin (cross-competing with C3a binding, suggesting a shared or overlapping binding site distinct from the C5a site), demonstrating C5L2 as a potential low-affinity receptor for C4a. Radioligand cross-competition binding assay with C5L2-transfected RBL-2H3 cells; [125I]-C5a and C3a displacement by C4a The Journal of biological chemistry Medium 11773063
2002 Bone marrow-derived macrophages synthesize and locally deposit C4 protein in splenic germinal centers; transfer of wild-type macrophages (or whole bone marrow) into C4-knockout mice restored C4 mRNA (detected by in situ hybridization), C4 protein deposits in follicles (immunofluorescence), and humoral immune responses to both soluble antigen and HSV-1, demonstrating that locally produced (macrophage-derived) C4 is sufficient for complement-dependent humoral immunity even in the absence of serum C4. Bone marrow reconstitution of C4-/- mice, immunization with NP5-KLH and HSV-1 infection, antibody titer measurement, in situ hybridization, immunofluorescence staining, cell sorting with RT-PCR Journal of immunology High 12421924
2016 C4A expression in the brain (determined by structural alleles of the C4 locus) promotes synapse elimination during postnatal development; C4 protein localizes to neuronal synapses, dendrites, axons, and cell bodies in humans; in mice, C4 mediates complement-dependent synaptic pruning, and higher C4A expression associates with schizophrenia risk in proportion to its level of brain expression. Human brain C4A/C4B expression quantification by allele-specific RNA-seq; C4 immunohistochemistry in human brain; mouse genetic model (C4-knockout and C4-overexpressing) with synapse counting by immunofluorescence; population genetic association Nature High 26814963
2020 C4A and C4B protein levels are higher in cerebrospinal fluid and plasma of men than women aged 20–50; common C4A/C4B allele combinations generate up to 14-fold variation in SLE risk and 31-fold variation in Sjögren's syndrome risk in men, with C4A acting more protectively than C4B against these autoimmune diseases while the same alleles increase schizophrenia risk; this sex-differential effect parallels sex differences in complement protein levels. Large-scale population genetic association study with definitive C4 structural genotyping; CSF and plasma C4/C3 protein level measurement stratified by sex and age Nature High 32499649
2021 Genetically predicted higher brain C4A expression associates with higher TSPO (microglial marker) binding on PET imaging and altered hippocampal morphology (reduced surface area and medial displacement in CA1) in living humans, suggesting C4A-mediated microglial activation and synapse elimination affect hippocampal structure in vivo. Genetically predicted C4A expression from structural alleles; [18F]FEPPA TSPO-PET imaging; MRI-based hippocampal morphometry in 111 participants Biological psychiatry Medium 34456009
1988 Tissue-specific expression of mouse C4 and the highly homologous Slp gene was characterized: C4 is expressed at high levels in liver and peritoneal macrophages, with lower but detectable levels in mammary gland, lung, spleen, kidney, testis, brain, heart, and submaxillary gland; regulatory differences between C4 and Slp vary across tissues and are controlled by distinct cis-acting and trans-acting factors in each tissue context. Northern blotting using C4/Slp-distinguishing probe across multiple mouse tissues; congenic strain comparison Nucleic acids research Medium 3405752
1998 Human astrocytes constitutively express C4 mRNA and protein; interferon-gamma upregulates C4 expression while IL-1beta inhibits it; C4 immunoreactivity was localized to GFAP-positive astrocytes when protein secretion was blocked, establishing astrocytes as a cellular source of complement C4 in the CNS. RT-PCR, ELISA, immunocytochemistry, immunoblot in primary human astrocytes with cytokine treatments; protein secretion inhibition Brain research Medium 9795119

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Schizophrenia risk from complex variation of complement component 4. Nature 1806 26814963
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2003 Identification and quantification of N-linked glycoproteins using hydrazide chemistry, stable isotope labeling and mass spectrometry. Nature biotechnology 1176 12754519
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2011 Antimicrobial peptides: key components of the innate immune system. Critical reviews in biotechnology 565 22074402
2012 Photorespiration and the evolution of C4 photosynthesis. Annual review of plant biology 474 22404472
2013 Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nature genetics 463 23535732
2004 The lectin-complement pathway--its role in innate immunity and evolution. Immunological reviews 443 15199963
1984 The structural basis of the multiple forms of human complement component C4. Cell 435 6546707
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
1984 A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature 406 6559257
2007 Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. American journal of human genetics 370 17503323
2005 Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry. Journal of proteome research 350 16335952
1984 A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. The EMBO journal 296 6332733
2018 Enhancer Activity Requires CBP/P300 Bromodomain-Dependent Histone H3K27 Acetylation. Cell reports 274 30110629
2022 EWSR1-induced circNEIL3 promotes glioma progression and exosome-mediated macrophage immunosuppressive polarization via stabilizing IGF2BP3. Molecular cancer 257 35031058
2004 An investigation into the human serum "interactome". Electrophoresis 247 15174051
1967 Formation and functional significance of a molecular complex derived from the second and the fourth component of human complement. The Journal of experimental medicine 245 6019133
2003 The DNA sequence and analysis of human chromosome 6. Nature 242 14574404
1984 The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. Journal of immunology (Baltimore, Md. : 1950) 227 6609966
2002 C4-dicarboxylate carriers and sensors in bacteria. Biochimica et biophysica acta 210 11803016
2010 Setaria viridis: a model for C4 photosynthesis. The Plant cell 206 20693355
1986 Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. The EMBO journal 197 2431902
2013 International Union of Basic and Clinical Pharmacology. [corrected]. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacological reviews 195 23383423
2020 Complement genes contribute sex-biased vulnerability in diverse disorders. Nature 189 32499649
2001 The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). The Journal of biological chemistry 189 11773063
2010 An mRNA blueprint for C4 photosynthesis derived from comparative transcriptomics of closely related C3 and C4 species. Plant physiology 188 20543093
2003 Paternal, maternal, and biparental molecular markers provide unique windows onto the evolutionary history of macaque monkeys. Evolution; international journal of organic evolution 175 12894949
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2020 UFMylation maintains tumour suppressor p53 stability by antagonizing its ubiquitination. Nature cell biology 168 32807901
2010 A human MAP kinase interactome. Nature methods 165 20936779
2011 Evolution of C4 photosynthesis in the genus Flaveria: how many and which genes does it take to make C4? The Plant cell 153 21705644
2011 C4 cycles: past, present, and future research on C4 photosynthesis. The Plant cell 141 22128120
1984 Preferential generation of leukotriene C4 by human eosinophils. Clinical and experimental immunology 136 6086189
1974 Biochemical and cytological relationships in C4 plants. Planta 134 24442564
2001 MOLECULAR ENGINEERING OF C4 PHOTOSYNTHESIS. Annual review of plant physiology and plant molecular biology 120 11337400
1987 Deletion of C4A genes in patients with systemic lupus erythematosus. Arthritis and rheumatism 114 3499152
1989 Analysis of C4-dicarboxylate transport genes in Rhizobium meliloti. Molecular microbiology 110 2546011
2016 Strategies for improving C4 photosynthesis. Current opinion in plant biology 103 27127850
2010 What can enzymes of C₄ photosynthesis do for C₃ plants under stress? Plant science : an international journal of experimental plant biology 103 21421406
2021 Complement C4, Infections, and Autoimmune Diseases. Frontiers in immunology 102 34335607
2014 Optimal translational termination requires C4 lysyl hydroxylation of eRF1. Molecular cell 93 24486019
2011 Enhancing drought tolerance in C(4) crops. Journal of experimental botany 93 21511912
1983 Complement allotyping in SLE: association with C4A null. Australian and New Zealand journal of medicine 85 6606418
2003 Evolution of C4 phosphoenolpyruvate carboxylase. Archives of biochemistry and biophysics 84 12781769
2016 Photorespiration connects C3 and C4 photosynthesis. Journal of experimental botany 81 26912798
2009 Ecological selection pressures for C4 photosynthesis in the grasses. Proceedings. Biological sciences 81 19324795
2003 Cold tolerance of C4 photosynthesis in Miscanthus x giganteus: adaptation in amounts and sequence of C4 photosynthetic enzymes. Plant physiology 77 12857847
1984 Structure and organization of the C4 genes. Philosophical transactions of the Royal Society of London. Series B, Biological sciences 74 6149580
2008 Overproduction of C4 photosynthetic enzymes in transgenic rice plants: an approach to introduce the C4-like photosynthetic pathway into rice. Journal of experimental botany 71 18316317
1984 Human C4 haplotypes with duplicated C4A or C4B. American journal of human genetics 69 6607672
2014 Deconstructing Kranz anatomy to understand C4 evolution. Journal of experimental botany 65 24799561
2012 Molecular evolution of genes recruited into C₄ photosynthesis. Trends in plant science 65 22326564
1989 C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus. Immunogenetics 65 2568334
1993 Early-onset autoimmune hepatitis is associated with a C4A gene deletion. Gastroenterology 64 8482459
1980 Activation of the fourth component of complement (C4): assessment by rocket immunoelectrophoresis and correlation with the metabolism of C4. Journal of immunology (Baltimore, Md. : 1950) 61 7373050
2011 Stabilization of C4a-hydroperoxyflavin in a two-component flavin-dependent monooxygenase is achieved through interactions at flavin N5 and C4a atoms. The Journal of biological chemistry 60 21680741
2004 Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus. Journal of immunology (Baltimore, Md. : 1950) 56 15294999
1981 Complete primary structure of human C4a anaphylatoxin. The Journal of biological chemistry 56 6167582
2006 Real-time PCR quantification of human complement C4A and C4B genes. BMC genetics 55 16403222
1993 Clinical expression of systemic lupus erythematosus in patients with C4A deficiency. Medicine 55 8341140
2009 Crystallographic, spectroscopic, and computational analysis of a flavin C4a-oxygen adduct in choline oxidase. Biochemistry 54 19133805
2013 Parallel recruitment of multiple genes into c4 photosynthesis. Genome biology and evolution 52 24179135
1992 Homologous genes for the C4 isoform of phosphoenolpyruvate carboxylase in a C3 and a C4 Flaveria species. Molecular & general genetics : MGG 49 1508152
2009 Geminivirus C4 protein alters Arabidopsis development. Protoplasma 48 20091067
2015 Identification of Photosynthesis-Associated C4 Candidate Genes through Comparative Leaf Gradient Transcriptome in Multiple Lineages of C3 and C4 Species. PloS one 47 26465154
2012 The dicotyledonous NAD malic enzyme C4 plant Cleome gynandra displays age-dependent plasticity of C4 decarboxylation biochemistry. Plant biology (Stuttgart, Germany) 47 22289126
1990 Differences between C4A and C4B in the handling of immune complexes: the enhancement of CR1 binding is more important than the inhibition of immunoprecipitation. Clinical and experimental immunology 47 2138067
2014 Photosynthesis of C3, C3-C4, and C4 grasses at glacial CO2. Journal of experimental botany 46 24723409
2003 Leukotriene C(4) synthase. Prostaglandins, leukotrienes, and essential fatty acids 46 12895593
2003 Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex. Progress in nucleic acid research and molecular biology 46 14604014
2000 Biological activities of recombinant chicken leptin C4S analog compared with unmodified leptins. American journal of physiology. Endocrinology and metabolism 45 10893330
2013 A recombinant begomovirus resulting from exchange of the C4 gene. The Journal of general virology 44 23720217
2016 Walking the C4 pathway: past, present, and future. Journal of experimental botany 43 27059273
1990 The c4 repressors of bacteriophages P1 and P7 are antisense RNAs. Cell 43 1696181
2016 Photosynthesis in C3-C4 intermediate Moricandia species. Journal of experimental botany 42 28110276
2002 Transport of leukotriene C4 and structurally related conjugates. Vitamins and hormones 42 11898391
1990 Lack of gene deletion for complement C4A deficiency in Japanese patients with systemic lupus erythematosus. The Journal of rheumatology 42 1976809
2002 Maize C4 and non-C4 NADP-dependent malic enzymes are encoded by distinct genes derived from a plastid-localized ancestor. Plant molecular biology 41 12374297
2002 C4 mechanisms in aquatic angiosperms: comparisons with terrestrial C4 systems. Functional plant biology : FPB 41 32689483
1981 Genetic analysis of C4 deficiency. The Journal of clinical investigation 41 7451653
2019 Evolution of C4 photosynthesis predicted by constraint-based modelling. eLife 40 31799932
2006 Immunoglobulins and complement factor C4 in adult rhinosinusitis. Clinical and experimental immunology 40 16879240
2017 Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients. Current Alzheimer research 39 27758680
2002 Macrophage-derived complement component C4 can restore humoral immunity in C4-deficient mice. Journal of immunology (Baltimore, Md. : 1950) 39 12421924
1972 Biosynthesis of C4 (fourth component of complement) by hybrids of C4-deficient guinea pig cells and HeLa cells. Science (New York, N.Y.) 39 5033180
2002 Are crassulacean acid metabolism and C4 photosynthesis incompatible? Functional plant biology : FPB 38 32689525
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