LOCUS       NP_009224               1744 aa            linear   PRI 03-SEP-2024
DEFINITION  complement C4-A isoform 1 preproprotein [Homo sapiens].
ACCESSION   NP_009224 XP_003403837 XP_003960095 XP_006726010 XP_011546427
VERSION     NP_009224.2
DBSOURCE    REFSEQ: accession NM_007293.3
KEYWORDS    RefSeq; MANE Select.
SOURCE      Homo sapiens (human)
  ORGANISM  Homo sapiens
            Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
            Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
            Catarrhini; Hominidae; Homo.
REFERENCE   1  (residues 1 to 1744)
  AUTHORS   Mariaselvam,C.M., Seth,G., Kavadichanda,C., Boukouaci,W., Wu,C.L.,
            Costes,B., Thabah,M.M., Krishnamoorthy,R., Leboyer,M., Negi,V.S.
            and Tamouza,R.
  TITLE     Low C4A copy numbers and higher HERV gene insertion contributes to
            increased risk of SLE, with absence of association with disease
            phenotype and disease activity
  JOURNAL   Immunol Res 72 (4), 697-706 (2024)
   PUBMED   38594415
  REMARK    GeneRIF: Low C4A copy numbers and higher HERV gene insertion
            contributes to increased risk of SLE, with absence of association
            with disease phenotype and disease activity.
REFERENCE   2  (residues 1 to 1744)
  AUTHORS   Hernandez,L.M., Kim,M., Zhang,P., Bethlehem,R.A.I., Hoftman,G.,
            Loughnan,R., Smith,D., Bookheimer,S.Y., Fan,C.C., Bearden,C.E.,
            Thompson,W.K. and Gandal,M.J.
  TITLE     Multi-ancestry phenome-wide association of complement component 4
            variation with psychiatric and brain phenotypes in youth
  JOURNAL   Genome Biol 24 (1), 42 (2023)
   PUBMED   36882872
  REMARK    GeneRIF: Multi-ancestry phenome-wide association of complement
            component 4 variation with psychiatric and brain phenotypes in
            youth.
            Publication Status: Online-Only
REFERENCE   3  (residues 1 to 1744)
  AUTHORS   Gracias,J., Orhan,F., Horbeck,E., Holmen-Larsson,J.,
            Khanlarkani,N., Malwade,S., Goparaju,S.K., Schwieler,L.,
            Demirel,I.S., Fu,T., Fatourus-Bergman,H., Pelanis,A., Goold,C.P.,
            Goulding,A., Annerbrink,K., Isgren,A., Sparding,T., Schalling,M.,
            Yanez,V.A.C., Gopfert,J.C., Nilsson,J., Brinkmalm,A., Blennow,K.,
            Zetterberg,H., Engberg,G., Piehl,F., Sheridan,S.D., Perlis,R.H.,
            Cervenka,S., Erhardt,S., Landen,M. and Sellgren,C.M.
  TITLE     Cerebrospinal fluid concentration of complement component 4A is
            increased in first episode schizophrenia
  JOURNAL   Nat Commun 13 (1), 6427 (2022)
   PUBMED   36329007
  REMARK    GeneRIF: Cerebrospinal fluid concentration of complement component
            4A is increased in first episode schizophrenia.
            Publication Status: Online-Only
REFERENCE   4  (residues 1 to 1744)
  AUTHORS   Pasupuleti,M., Walse,B., Nordahl,E.A., Morgelin,M., Malmsten,M. and
            Schmidtchen,A.
  TITLE     Preservation of antimicrobial properties of complement peptide C3a,
            from invertebrates to humans
  JOURNAL   J Biol Chem 282 (4), 2520-2528 (2007)
   PUBMED   17132627
  REMARK    GeneRIF: Complement components C3a and C4a, but not C5a, display
            antimicrobial activity against P. aeruginosa, E. coli, B. subtilis,
            and C. albicans.
REFERENCE   5  (residues 1 to 1744)
  AUTHORS   Anderson,M.J., Milner,C.M., Cotton,R.G. and Campbell,R.D.
  TITLE     The coding sequence of the hemolytically inactive C4A6 allotype of
            human complement component C4 reveals that a single arginine to
            tryptophan substitution at beta-chain residue 458 is the likely
            cause of the defect
  JOURNAL   J Immunol 148 (9), 2795-2802 (1992)
   PUBMED   1573268
REFERENCE   6  (residues 1 to 1744)
  AUTHORS   Yu,C.Y.
  TITLE     The complete exon-intron structure of a human complement component
            C4A gene. DNA sequences, polymorphism, and linkage to the
            21-hydroxylase gene
  JOURNAL   J Immunol 146 (3), 1057-1066 (1991)
   PUBMED   1988494
REFERENCE   7  (residues 1 to 1744)
  AUTHORS   Palsdottir,A., Fossdal,R., Arnason,A., Edwards,J.H. and Jensson,O.
  TITLE     Heterogeneity of human C4 gene size. A large intron (6.5 kb) is
            present in all C4A genes and some C4B genes
  JOURNAL   Immunogenetics 25 (5), 299-304 (1987)
   PUBMED   2883116
REFERENCE   8  (residues 1 to 1744)
  AUTHORS   Yu,C.Y., Belt,K.T., Giles,C.M., Campbell,R.D. and Porter,R.R.
  TITLE     Structural basis of the polymorphism of human complement components
            C4A and C4B: gene size, reactivity and antigenicity
  JOURNAL   EMBO J 5 (11), 2873-2881 (1986)
   PUBMED   2431902
REFERENCE   9  (residues 1 to 1744)
  AUTHORS   Belt,K.T., Carroll,M.C. and Porter,R.R.
  TITLE     The structural basis of the multiple forms of human complement
            component C4
  JOURNAL   Cell 36 (4), 907-914 (1984)
   PUBMED   6546707
REFERENCE   10 (residues 1 to 1744)
  AUTHORS   Fearon,D.T.
  TITLE     Activation of the alternative complement pathway
  JOURNAL   CRC Crit Rev Immunol 1 (1), 1-32 (1979)
   PUBMED   162484
  REMARK    Review article
COMMENT     REVIEWED REFSEQ: This record has been curated by NCBI staff. The
            reference sequence was derived from DA304049.1, K02403.1,
            AL645922.12, BC146673.1 and BC016933.1.
            
            On or before Mar 22, 2015 this sequence version replaced
            XP_011546427.1, XP_006726010.1, XP_003960095.1, XP_003403837.1,
            NP_009224.1.
            
            Summary: This gene encodes the acidic form of complement factor 4,
            part of the classical activation pathway. The protein is expressed
            as a single chain precursor which is proteolytically cleaved into a
            trimer of alpha, beta, and gamma chains prior to secretion. The
            trimer provides a surface for interaction between the
            antigen-antibody complex and other complement components. The alpha
            chain is cleaved to release C4 anaphylatoxin, an antimicrobial
            peptide and a mediator of local inflammation. Deficiency of this
            protein is associated with systemic lupus erythematosus and type I
            diabetes mellitus. This gene localizes to the major
            histocompatibility complex (MHC) class III region on chromosome 6.
            Varying haplotypes of this gene cluster exist, such that
            individuals may have 1, 2, or 3 copies of this gene. Two transcript
            variants encoding different isoforms have been found for this gene.
            [provided by RefSeq, Nov 2014].
            
            Transcript Variant: This variant (1) represents the longer
            transcript and encodes the longer isoform (1).
            
            Sequence Note: This RefSeq record represents the C4A*001.1.1
            allele.
            
            Publication Note:  This RefSeq record includes a subset of the
            publications that are available for this gene. Please see the Gene
            record to access additional publications.
            
            ##Evidence-Data-START##
            Transcript exon combination :: SRR1660807.237372.1,
                                           SRR1803615.258018.1 [ECO:0000332]
            ##Evidence-Data-END##
            
            ##RefSeq-Attributes-START##
            MANE Ensembl match                 :: ENST00000428956.7/
                                                  ENSP00000396688.2
            Protein has antimicrobial activity :: PMID: 17132627
            RefSeq Select criteria             :: based on manual assertion,
                                                  conservation, expression,
                                                  longest protein
            ##RefSeq-Attributes-END##
FEATURES             Location/Qualifiers
     source          1..1744
                     /organism="Homo sapiens"
                     /db_xref="taxon:9606"
                     /chromosome="6"
                     /map="6p21.33"
     Protein         1..1744
                     /product="complement C4-A isoform 1 preproprotein"
                     /note="acidic C4; Rodgers form of C4; C4A anaphylatoxin;
                     complement C4-A; acidic complement C4; C3 and PZP-like
                     alpha-2-macroglobulin domain-containing protein 2; MHC
                     class III region complement; complement component 4A
                     (Rodgers blood group); complement C4A (Rodgers blood
                     group)"
                     /calculated_mol_wt=190535
     sig_peptide     1..19
                     /inference="COORDINATES: ab initio prediction:SignalP:6.0"
                     /calculated_mol_wt=2270
     proprotein      20..1744
                     /product="complement C4-A isoform 1 proprotein"
                     /calculated_mol_wt=190535
     Region          <138..1336
                     /region_name="YfaS"
                     /note="Uncharacterized conserved protein YfaS,
                     alpha-2-macroglobulin family [General function prediction
                     only]; COG2373"
                     /db_xref="CDD:441940"
     Region          141..233
                     /region_name="A2M_N"
                     /note="MG2 domain; pfam01835"
     Region          478..610
                     /region_name="A2M_N_2"
                     /note="Alpha-2-macroglobulin family N-terminal region;
                     pfam07703"
     mat_peptide     680..756
                     /product="C4a anaphylatoxin"
                     /experiment="DESCRIPTION:antimicrobial
                     peptide[PMID:17132627]"
                     /calculated_mol_wt=8764
     Region          686..750
                     /region_name="ANATO"
                     /note="Anaphylatoxin homologous domain; C3a, C4a and C5a
                     anaphylatoxins are protein fragments generated
                     enzymatically in serum during activation of complement
                     molecules C3, C4, and C5. They induce smooth muscle
                     contraction. These fragments are homologous to...;
                     cd00017"
                     /db_xref="CDD:237984"
     Region          686..750
                     /region_name="ANATO"
                     /note="Anaphylatoxin homologous domain; C3a, C4a and C5a
                     anaphylatoxins are protein fragments generated
                     enzymatically in serum during activation of complement
                     molecules C3, C4, and C5. They induce smooth muscle
                     contraction. These fragments are homologous to...;
                     cd00017"
     Region          781..869
                     /region_name="A2M"
                     /note="Alpha-2-macroglobulin family; pfam00207"
                     /db_xref="CDD:459711"
     Region          782..869
                     /region_name="A2M"
                     /note="Alpha-2-macroglobulin family; pfam00207"
     Region          982..1315
                     /region_name="TED_complement"
                     /note="A-macroglobulin TED domain; pfam07678"
                     /db_xref="CDD:462227"
     Region          996..1315
                     /region_name="complement_C3_C4_C5"
                     /note="Proteins similar to C3, C4 and C5 of vertebrate
                     complement. The vertebrate complement system, comprised of
                     a large number of distinct plasma proteins, is an effector
                     of both the acquired and innate immune systems. The point
                     of convergence of the...; cd02896"
     Site            order(1010,1012..1013,1016,1059,1069,1072,1122,1124..1125,
                     1299)
                     /site_type="other"
                     /note="surface patch"
     Site            order(1010..1013,1125)
                     /site_type="active"
     Site            1010..1013
                     /site_type="other"
                     /note="thioester region"
     Region          1051..1317
                     /region_name="A2M_comp"
                     /note="A-macroglobulin complement component; pfam07678"
     Site            order(1111,1115,1117,1125,1130..1131)
                     /site_type="other"
                     /note="specificity defining residues"
     Region          1481..1570
                     /region_name="A2M_recep"
                     /note="A-macroglobulin receptor binding domain; pfam07677"
                     /db_xref="CDD:462226"
     Region          1481..1570
                     /region_name="A2M_recep"
                     /note="A-macroglobulin receptor; pfam07677"
     Region          1588..1742
                     /region_name="NTR_complement_C4"
                     /note="NTR/C345C domain, complement C4 subfamily; The NTR
                     domain found in complement C4 is also known as the C345C
                     domain because it occurs at the C-terminus of complement
                     C3, C4 and C5. Complement C4 is a key player in the
                     activation of the component classical...; cd03584"
                     /db_xref="CDD:239639"
     Region          1588..1742
                     /region_name="NTR_complement_C4"
                     /note="NTR/C345C domain, complement C4 subfamily; The NTR
                     domain found in complement C4 is also known as the C345C
                     domain because it occurs at the C-terminus of complement
                     C3, C4 and C5. Complement C4 is a key player in the
                     activation of the component classical...; cd03584"
     CDS             1..1744
                     /gene="C4A"
                     /gene_synonym="C4; C4A2; C4A3; C4A4; C4A6; C4AD; C4S; CO4;
                     CPAMD2; RG"
                     /coded_by="NM_007293.3:52..5286"
                     /note="isoform 1 preproprotein is encoded by transcript
                     variant 1"
                     /db_xref="CCDS:CCDS47404.1"
                     /db_xref="GeneID:720"
                     /db_xref="HGNC:HGNC:1323"
                     /db_xref="MIM:120810"
ORIGIN      
        1 mrllwgliwa ssfftlslqk prlllfspsv vhlgvplsvg vqlqdvprgq vvkgsvflrn
       61 psrnnvpcsp kvdftlsser dfallslqvp lkdakscglh qllrgpevql vahspwlkds
      121 lsrttniqgi nllfssrrgh lflqtdqpiy npgqrvryrv faldqkmrps tdtitvmven
      181 shglrvrkke vympssifqd dfvipdisep gtwkisarfs dglesnsstq fevkkyvlpn
      241 fevkitpgkp yiltvpghld emqldiqary iygkpvqgva yvrfgllded gkktffrgle
      301 sqtklvngqs hislskaefq daleklnmgi tdlqglrlyv aaaiiespgg emeeaeltsw
      361 yfvsspfsld lsktkrhlvp gapfllqalv remsgspasg ipvkvsatvs spgsvpevqd
      421 iqqntdgsgq vsipiiipqt iselqlsvsa gsphpaiarl tvaappsggp gflsierpds
      481 rpprvgdtln lnlravgsga tfshyyymil srgqivfmnr epkrtltsvs vfvdhhlaps
      541 fyfvafyyhg dhpvanslrv dvqagacegk lelsvdgakq yrngesvklh letdslalva
      601 lgaldtalya agskshkpln mgkvfeamns ydlgcgpggg dsalqvfqaa glafsdgdqw
      661 tlsrkrlscp kekttrkkrn vnfqkainek lgqyasptak rccqdgvtrl pmmrsceqra
      721 arvqqpdcre pflsccqfae slrkksrdkg qaglqralei lqeedlided dipvrsffpe
      781 nwlwrvetvd rfqiltlwlp dslttweihg lslsktkglc vatpvqlrvf refhlhlrlp
      841 msvrrfeqle lrpvlynyld knltvsvhvs pveglclagg gglaqqvlvp agsarpvafs
      901 vvptaaaavs lkvvargsfe fpvgdavskv lqiekegaih reelvyelnp ldhrgrtlei
      961 pgnsdpnmip dgdfnsyvrv tasdpldtlg segalspggv asllrlprgc geqtmiylap
     1021 tlaasryldk teqwstlppe tkdhavdliq kgymriqqfr kadgsyaawl srdsstwlta
     1081 fvlkvlslaq eqvggspekl qetsnwllsq qqadgsfqdp cpvldrsmqg glvgndetva
     1141 ltafvtialh hglavfqdeg aeplkqrvea siskansflg ekasagllga haaaitayal
     1201 tltkapvdll gvahnnlmam aqetgdnlyw gsvtgsqsna vsptpaprnp sdpmpqapal
     1261 wiettayall hlllhegkae madqasawlt rqgsfqggfr stqdtviald alsaywiash
     1321 tteerglnvt lsstgrngfk shalqlnnrq irgleeelqf slgskinvkv ggnskgtlkv
     1381 lrtynvldmk nttcqdlqie vtvkghveyt meanedyedy eydelpakdd pdaplqpvtp
     1441 lqlfegrrnr rrreapkvve eqesrvhytv ciwrngkvgl sgmaiadvtl lsgfhalrad
     1501 lekltslsdr yvshfetegp hvllyfdsvp tsrecvgfea vqevpvglvq pasatlydyy
     1561 nperrcsvfy gapsksrlla tlcsaevcqc aegkcprqrr alerglqded gyrmkfacyy
     1621 prveygfqvk vlredsraaf rlfetkitqv lhftkdvkaa anqmrnflvr ascrlrlepg
     1681 keylimgldg atydleghpq ylldsnswie empserlcrs trqraacaql ndflqeygtq
     1741 gcqv
//
