ITIH3_HUMAN
ID ITIH3_HUMAN Reviewed; 890 AA.
AC Q06033; Q3B7H5; Q53F06; Q6LAM2; Q99085;
DT 15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT 04-DEC-2007, sequence version 2.
DT 03-AUG-2022, entry version 165.
DE RecName: Full=Inter-alpha-trypsin inhibitor heavy chain H3;
DE Short=ITI heavy chain H3;
DE Short=ITI-HC3;
DE Short=Inter-alpha-inhibitor heavy chain 3;
DE AltName: Full=Serum-derived hyaluronan-associated protein;
DE Short=SHAP;
DE Flags: Precursor;
GN Name=ITIH3;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT LYS-315.
RC TISSUE=Liver;
RX PubMed=7681778; DOI=10.1111/j.1432-1033.1993.tb17717.x;
RA Bourguignon J., Diarra-Mehrpour M., Thiberville L., Bost F., Sesboue R.,
RA Martin J.-P.;
RT "Human pre-alpha-trypsin inhibitor-precursor heavy chain. cDNA and deduced
RT amino-acid sequence.";
RL Eur. J. Biochem. 212:771-776(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=9756925; DOI=10.1074/jbc.273.41.26809;
RA Diarra-Mehrpour M., Sarafan N., Bourguignon J., Bonnet F., Bost F.,
RA Martin J.-P.;
RT "Human inter-alpha-trypsin inhibitor heavy chain H3 gene. Genomic
RT organization, promoter analysis, and gene linkage.";
RL J. Biol. Chem. 273:26809-26819(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-27 (ISOFORM 2).
RX PubMed=7522574; DOI=10.1016/0167-4781(94)90087-6;
RA Diarra-Mehrpour M., Bourguignon J., Sarafan N., Bost F., Sesbouee R.,
RA Muschio-Bonnet F., Martin J.-P.;
RT "Tandem orientation of the inter-alpha-trypsin inhibitor heavy chain H1 and
RT H3 genes.";
RL Biochim. Biophys. Acta 1219:551-554(1994).
RN [7]
RP PROTEIN SEQUENCE OF 34-53; 467-481 AND 501-519, IDENTIFICATION IN
RP PRE-ALPHA-INHIBITOR COMPLEX, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=2476436; DOI=10.1016/s0021-9258(18)71575-5;
RA Enghild J.J., Thoegersen I.B., Pizzo S.V., Salvesen G.;
RT "Analysis of inter-alpha-trypsin inhibitor and a novel trypsin inhibitor,
RT pre-alpha-trypsin inhibitor, from human plasma. Polypeptide chain
RT stoichiometry and assembly by glycan.";
RL J. Biol. Chem. 264:15975-15981(1989).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 345-890 (ISOFORMS 1/2).
RC TISSUE=Liver;
RX PubMed=2465147; DOI=10.1111/j.1432-1033.1989.tb14532.x;
RA Diarra-Mehrpour M., Bourguignon J., Sesboue R., Mattei M.-G., Passage E.,
RA Salier J.-P., Martin J.-P.;
RT "Human plasma inter-alpha-trypsin inhibitor is encoded by four genes on
RT three chromosomes.";
RL Eur. J. Biochem. 179:147-154(1989).
RN [9]
RP PROTEIN SEQUENCE OF 635-651, AND CROSS-LINK SITE TO BIKUNIN.
RX PubMed=1898736; DOI=10.1016/s0021-9258(17)35235-3;
RA Enghild J.J., Salvesen G., Hefta S.A., Thoegersen I.B., Rutherfurd S.,
RA Pizzo S.V.;
RT "Chondroitin 4-sulfate covalently cross-links the chains of the human blood
RT protein pre-alpha-inhibitor.";
RL J. Biol. Chem. 266:747-751(1991).
RN [10]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-91 AND ASN-580.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., Moore R.J.,
RA Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
CC -!- FUNCTION: May act as a carrier of hyaluronan in serum or as a binding
CC protein between hyaluronan and other matrix protein, including those on
CC cell surfaces in tissues to regulate the localization, synthesis and
CC degradation of hyaluronan which are essential to cells undergoing
CC biological processes.
CC -!- SUBUNIT: I-alpha-I plasma protease inhibitors are assembled from one or
CC two heavy chains (HC) and one light chain, bikunin. Pre-alpha-inhibitor
CC (P-alpha-I) is composed of ITIH3/HC3 and bikunin.
CC {ECO:0000269|PubMed:2476436}.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q06033-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q06033-2; Sequence=VSP_029842;
CC -!- PTM: Heavy chains are linked to bikunin via chondroitin 4-sulfate
CC esterified to the alpha-carboxyl of the C-terminal aspartate after
CC propeptide cleavage.
CC -!- SIMILARITY: Belongs to the ITIH family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA32821.1; Type=Frameshift; Evidence={ECO:0000305};
CC Sequence=CAA47439.1; Type=Frameshift; Evidence={ECO:0000305};
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DR EMBL; X67055; CAA47439.1; ALT_FRAME; mRNA.
DR EMBL; X99854; CAC79611.1; -; Genomic_DNA.
DR EMBL; AK222757; BAD96477.1; -; mRNA.
DR EMBL; AK223483; BAD97203.1; -; mRNA.
DR EMBL; AC006254; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC107604; AAI07605.1; -; mRNA.
DR EMBL; BC107605; AAI07606.1; -; mRNA.
DR EMBL; BC107814; AAI07815.1; -; mRNA.
DR EMBL; X14690; CAA32821.1; ALT_FRAME; mRNA.
DR CCDS; CCDS46845.1; -. [Q06033-1]
DR PIR; S30350; S30350.
DR RefSeq; NP_002208.3; NM_002217.3. [Q06033-1]
DR AlphaFoldDB; Q06033; -.
DR SMR; Q06033; -.
DR BioGRID; 109905; 36.
DR IntAct; Q06033; 7.
DR MINT; Q06033; -.
DR STRING; 9606.ENSP00000415769; -.
DR DrugBank; DB01593; Zinc.
DR DrugBank; DB14487; Zinc acetate.
DR DrugBank; DB14533; Zinc chloride.
DR DrugBank; DB14548; Zinc sulfate, unspecified form.
DR CarbonylDB; Q06033; -.
DR GlyConnect; 1421; 10 N-Linked glycans (1 site).
DR GlyGen; Q06033; 2 sites, 10 N-linked glycans (1 site).
DR iPTMnet; Q06033; -.
DR PhosphoSitePlus; Q06033; -.
DR BioMuta; ITIH3; -.
DR DMDM; 166203665; -.
DR EPD; Q06033; -.
DR jPOST; Q06033; -.
DR MassIVE; Q06033; -.
DR MaxQB; Q06033; -.
DR PaxDb; Q06033; -.
DR PeptideAtlas; Q06033; -.
DR PRIDE; Q06033; -.
DR ProteomicsDB; 58409; -. [Q06033-1]
DR ProteomicsDB; 58410; -. [Q06033-2]
DR Antibodypedia; 7471; 109 antibodies from 23 providers.
DR DNASU; 3699; -.
DR Ensembl; ENST00000449956.3; ENSP00000415769.2; ENSG00000162267.13. [Q06033-1]
DR GeneID; 3699; -.
DR KEGG; hsa:3699; -.
DR MANE-Select; ENST00000449956.3; ENSP00000415769.2; NM_002217.4; NP_002208.3.
DR UCSC; uc003dfv.3; human. [Q06033-1]
DR CTD; 3699; -.
DR DisGeNET; 3699; -.
DR GeneCards; ITIH3; -.
DR HGNC; HGNC:6168; ITIH3.
DR HPA; ENSG00000162267; Tissue enriched (liver).
DR MIM; 146650; gene.
DR neXtProt; NX_Q06033; -.
DR OpenTargets; ENSG00000162267; -.
DR PharmGKB; PA29966; -.
DR VEuPathDB; HostDB:ENSG00000162267; -.
DR eggNOG; ENOG502QPS2; Eukaryota.
DR GeneTree; ENSGT00940000154554; -.
DR InParanoid; Q06033; -.
DR OMA; HPIHQDF; -.
DR OrthoDB; 955432at2759; -.
DR PhylomeDB; Q06033; -.
DR TreeFam; TF328982; -.
DR PathwayCommons; Q06033; -.
DR Reactome; R-HSA-114608; Platelet degranulation.
DR SignaLink; Q06033; -.
DR BioGRID-ORCS; 3699; 15 hits in 1065 CRISPR screens.
DR ChiTaRS; ITIH3; human.
DR GeneWiki; ITIH3; -.
DR GenomeRNAi; 3699; -.
DR Pharos; Q06033; Tbio.
DR PRO; PR:Q06033; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q06033; protein.
DR Bgee; ENSG00000162267; Expressed in right lobe of liver and 107 other tissues.
DR ExpressionAtlas; Q06033; baseline and differential.
DR Genevisible; Q06033; HS.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0031089; C:platelet dense granule lumen; TAS:Reactome.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0004867; F:serine-type endopeptidase inhibitor activity; IEA:UniProtKB-KW.
DR GO; GO:0030212; P:hyaluronan metabolic process; IEA:InterPro.
DR Gene3D; 3.40.50.410; -; 1.
DR InterPro; IPR010600; ITI_HC_C.
DR InterPro; IPR013694; VIT.
DR InterPro; IPR002035; VWF_A.
DR InterPro; IPR036465; vWFA_dom_sf.
DR Pfam; PF06668; ITI_HC_C; 1.
DR Pfam; PF08487; VIT; 1.
DR Pfam; PF00092; VWA; 1.
DR SMART; SM00609; VIT; 1.
DR SMART; SM00327; VWA; 1.
DR SUPFAM; SSF53300; SSF53300; 1.
DR PROSITE; PS51468; VIT; 1.
DR PROSITE; PS50234; VWFA; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Direct protein sequencing; Glycoprotein;
KW Protease inhibitor; Proteoglycan; Reference proteome; Secreted;
KW Serine protease inhibitor; Signal.
FT SIGNAL 1..20
FT /evidence="ECO:0000255"
FT PROPEP 21..34
FT /id="PRO_0000016529"
FT CHAIN 35..651
FT /note="Inter-alpha-trypsin inhibitor heavy chain H3"
FT /id="PRO_0000016530"
FT PROPEP 652..890
FT /id="PRO_0000016531"
FT DOMAIN 29..158
FT /note="VIT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00801"
FT DOMAIN 284..467
FT /note="VWFA"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00219"
FT MOD_RES 651
FT /note="Aspartate 1-(chondroitin 4-sulfate)-ester"
FT CARBOHYD 91
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT CARBOHYD 580
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:16335952"
FT VAR_SEQ 1..21
FT /note="MAFAWWPCLILALLSSLAASG -> MVALSHLGSALQLGSLC (in
FT isoform 2)"
FT /evidence="ECO:0000303|PubMed:7522574,
FT ECO:0000303|PubMed:7681778"
FT /id="VSP_029842"
FT VARIANT 315
FT /note="Q -> K (in dbSNP:rs3617)"
FT /evidence="ECO:0000269|PubMed:7681778"
FT /id="VAR_049647"
FT VARIANT 340
FT /note="T -> M (in dbSNP:rs35271262)"
FT /id="VAR_049648"
FT VARIANT 640
FT /note="P -> L (in dbSNP:rs60805548)"
FT /id="VAR_061275"
FT VARIANT 751
FT /note="T -> A (in dbSNP:rs9883888)"
FT /id="VAR_049649"
FT VARIANT 825
FT /note="R -> Q (in dbSNP:rs2710330)"
FT /id="VAR_049650"
FT VARIANT 858
FT /note="A -> V (in dbSNP:rs2710329)"
FT /id="VAR_049651"
FT CONFLICT 113
FT /note="K -> N (in Ref. 3; BAD97203/BAD96477)"
FT /evidence="ECO:0000305"
FT CONFLICT 348
FT /note="R -> K (in Ref. 8; CAA32821)"
FT /evidence="ECO:0000305"
FT CONFLICT 361
FT /note="N -> G (in Ref. 8; CAA32821)"
FT /evidence="ECO:0000305"
FT CONFLICT 515
FT /note="F -> L (in Ref. 2; CAC79611)"
FT /evidence="ECO:0000305"
FT CONFLICT 667
FT /note="F -> L (in Ref. 3; BAD97203/BAD96477)"
FT /evidence="ECO:0000305"
FT CONFLICT 716
FT /note="A -> R (in Ref. 1; CAA47439 and 8; CAA32821)"
FT /evidence="ECO:0000305"
FT CONFLICT 851
FT /note="Q -> H (in Ref. 8; CAA32821)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 890 AA; 99849 MW; 03B2B768784CB440 CRC64;
MAFAWWPCLI LALLSSLAAS GFPRSPFRLL GKRSLPEGVA NGIEVYSTKI NSKVTSRFAH
NVVTMRAVNR ADTAKEVSFD VELPKTAFIT NFTLTIDGVT YPGNVKEKEV AKKQYEKAVS
QGKTAGLVKA SGRKLEKFTV SVNVAAGSKV TFELTYEELL KRHKGKYEMY LKVQPKQLVK
HFEIEVDIFE PQGISMLDAE ASFITNDLLG SALTKSFSGK KGHVSFKPSL DQQRSCPTCT
DSLLNGDFTI TYDVNRESPG NVQIVNGYFV HFFAPQGLPV VPKNVAFVID ISGSMAGRKL
EQTKEALLRI LEDMQEEDYL NFILFSGDVS TWKEHLVQAT PENLQEARTF VKSMEDKGMT
NINDGLLRGI SMLNKAREEH RIPERSTSIV IMLTDGDANV GESRPEKIQE NVRNAIGGKF
PLYNLGFGNN LNYNFLENMA LENHGFARRI YEDSDADLQL QGFYEEVANP LLTGVEMEYP
ENAILDLTQN TYQHFYDGSE IVVAGRLVDE DMNSFKADVK GHGATNDLTF TEEVDMKEME
KALQERDYIF GNYIERLWAY LTIEQLLEKR KNAHGEEKEN LTARALDLSL KYHFVTPLTS
MVVTKPEDNE DERAIADKPG EDAEATPVSP AMSYLTSYQP PQNPYYYVDG DPHFIIQIPE
KDDALCFNID EAPGTVLRLI QDAVTGLTVN GQITGDKRGS PDSKTRKTYF GKLGIANAQM
DFQVEVTTEK ITLWNRAVPS TFSWLDTVTV TQDGLSMMIN RKNMVVSFGD GVTFVVVLHQ
VWKKHPVHRD FLGFYVVDSH RMSAQTHGLL GQFFQPFDFK VSDIRPGSDP TKPDATLVVK
NHQLIVTRGS QKDYRKDASI GTKVVCWFVH NNGEGLIDGV HTDYIVPNLF
