LRC33_HUMAN
ID LRC33_HUMAN Reviewed; 692 AA.
AC Q86YC3;
DT 25-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 03-AUG-2022, entry version 154.
DE RecName: Full=Transforming growth factor beta activator LRRC33 {ECO:0000305};
DE AltName: Full=Leucine-rich repeat-containing protein 33 {ECO:0000305};
DE AltName: Full=Negative regulator of reactive oxygen species {ECO:0000250|UniProtKB:Q8BMT4};
DE Flags: Precursor;
GN Name=NRROS {ECO:0000312|HGNC:HGNC:24613};
GN Synonyms=LRRC33 {ECO:0000303|PubMed:29909984, ECO:0000312|HGNC:HGNC:24613};
GN ORFNames=UNQ3030/PRO9833 {ECO:0000303|PubMed:12975309};
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 [LARGE SCALE MRNA].
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Ovary;
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 [4]
RP FUNCTION, TISSUE SPECIFICITY, INTERACTION WITH TOLL-LIKE RECEPTORS, AND
RP SUBCELLULAR LOCATION.
RX PubMed=23545260; DOI=10.1016/j.bbrc.2013.03.071;
RA Liu J., Zhang Z., Chai L., Che Y., Min S., Yang R.;
RT "Identification and characterization of a unique leucine-rich repeat
RT protein (LRRC33) that inhibits Toll-like receptor-mediated NF-kappa-B
RT activation.";
RL Biochem. Biophys. Res. Commun. 434:28-34(2013).
RN [5]
RP SUBCELLULAR LOCATION, INTERACTION WITH TGFB1, AND TISSUE SPECIFICITY.
RX PubMed=29909984; DOI=10.1016/j.cell.2018.05.027;
RA Qin Y., Garrison B.S., Ma W., Wang R., Jiang A., Li J., Mistry M.,
RA Bronson R.T., Santoro D., Franco C., Robinton D.A., Stevens B., Rossi D.J.,
RA Lu C., Springer T.A.;
RT "A milieu molecule for TGF-beta required for microglia function in the
RT nervous system.";
RL Cell 174:156-171(2018).
RN [6]
RP INVOLVEMENT IN SENEBAC, VARIANT SENEBAC 593-GLN--TYR-692 DEL, AND TISSUE
RP SPECIFICITY.
RX PubMed=32100099; DOI=10.1007/s00401-020-02137-7;
RA Smith C., McColl B.W., Patir A., Barrington J., Armishaw J., Clarke A.,
RA Eaton J., Hobbs V., Mansour S., Nolan M., Rice G.I., Rodero M.P.,
RA Seabra L., Uggenti C., Livingston J.H., Bridges L.R., Jeffrey I.J.M.,
RA Crow Y.J.;
RT "Biallelic mutations in NRROS cause an early onset lethal microgliopathy.";
RL Acta Neuropathol. 139:947-951(2020).
RN [7]
RP INVOLVEMENT IN SENEBAC, VARIANT SENEBAC PRO-10, AND SUBCELLULAR LOCATION.
RX PubMed=32197075; DOI=10.1016/j.ajhg.2020.02.014;
RA Dong X., Tan N.B., Howell K.B., Barresi S., Freeman J.L., Vecchio D.,
RA Piccione M., Radio F.C., Calame D., Zong S., Eggers S., Scheffer I.E.,
RA Tan T.Y., Van Bergen N.J., Tartaglia M., Christodoulou J., White S.M.;
RT "Bi-allelic LoF NRROS Variants Impairing Active TGF-beta1 Delivery Cause a
RT Severe Infantile-Onset Neurodegenerative Condition with Intracranial
RT Calcification.";
RL Am. J. Hum. Genet. 106:559-569(2020).
CC -!- FUNCTION: Key regulator of transforming growth factor beta-1 (TGFB1)
CC specifically required for microglia function in the nervous system (By
CC similarity). Required for activation of latent TGF-beta-1 in
CC macrophages and microglia: associates specifically via disulfide bonds
CC with the Latency-associated peptide (LAP), which is the regulatory
CC chain of TGFB1, and regulates integrin-dependent activation of TGF-
CC beta-1 (By similarity). TGF-beta-1 activation mediated by LRRC33/NRROS
CC is highly localized: there is little spreading of TGF-beta-1 activated
CC from one microglial cell to neighboring microglia, suggesting the
CC existence of localized and selective activation of TGF-beta-1 by
CC LRRC33/NRROS (By similarity). Indirectly plays a role in Toll-like
CC receptor (TLR) signaling: ability to inhibit TLR-mediated NF-kappa-B
CC activation and cytokine production is probably a consequence of its
CC role in TGF-beta-1 signaling (PubMed:23545260).
CC {ECO:0000250|UniProtKB:Q8BMT4, ECO:0000269|PubMed:23545260}.
CC -!- SUBUNIT: Interacts with TGFB1; associates via disulfide bonds with the
CC Latency-associated peptide chain (LAP) regulatory chain of TGFB1,
CC leading to regulate activation of TGF-beta-1 (PubMed:29909984).
CC Interacts (via LRR repeats) with TLR2, TLR3, TLR4, TLR9 and probably
CC other Toll-like receptors (PubMed:23545260). Interacts with CYBB/NOX2;
CC the interaction is direct (By similarity).
CC {ECO:0000250|UniProtKB:Q8BMT4, ECO:0000269|PubMed:23545260,
CC ECO:0000269|PubMed:29909984}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:23545260,
CC ECO:0000269|PubMed:29909984}; Single-pass type I membrane protein
CC {ECO:0000255}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:32197075}; Single-pass type I membrane protein
CC {ECO:0000255}.
CC -!- TISSUE SPECIFICITY: Mainly expressed in cells of hematopoietic origin
CC (PubMed:29909984). Highly expressed in bone marrow, thymus, liver,
CC lung, intestine and spleen (PubMed:23545260). In the brain, highly
CC expressed in microglia (PubMed:32100099). {ECO:0000269|PubMed:23545260,
CC ECO:0000269|PubMed:32100099}.
CC -!- DISEASE: Seizures, early-onset, with neurodegeneration and brain
CC calcification (SENEBAC) [MIM:618875]: An autosomal recessive
CC neurodegenerative disorder clinically characterized by refractory
CC seizures apparent in the first year of life, mild early developmental
CC delay, and developmental regression after seizure onset. Other features
CC include hypotonia, hyperreflexia, peripheral spasticity, poor eye
CC contact, absent speech, poor head control, and inability to walk. Brain
CC imaging shows reduced white matter volume with delayed myelination, and
CC punctate calcifications. {ECO:0000269|PubMed:32100099,
CC ECO:0000269|PubMed:32197075}. Note=The protein represented in this
CC entry is involved in disease pathogenesis.
CC -!- SIMILARITY: Belongs to the LRRC32/LRRC33 family. {ECO:0000305}.
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DR EMBL; AY358322; AAQ88688.1; -; mRNA.
DR EMBL; AC055725; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC044233; AAH44233.1; -; mRNA.
DR CCDS; CCDS3319.1; -.
DR RefSeq; NP_940967.1; NM_198565.2.
DR AlphaFoldDB; Q86YC3; -.
DR SMR; Q86YC3; -.
DR BioGRID; 131978; 37.
DR IntAct; Q86YC3; 17.
DR STRING; 9606.ENSP00000328625; -.
DR GlyGen; Q86YC3; 11 sites.
DR iPTMnet; Q86YC3; -.
DR PhosphoSitePlus; Q86YC3; -.
DR BioMuta; NRROS; -.
DR DMDM; 74762465; -.
DR EPD; Q86YC3; -.
DR jPOST; Q86YC3; -.
DR MassIVE; Q86YC3; -.
DR MaxQB; Q86YC3; -.
DR PaxDb; Q86YC3; -.
DR PeptideAtlas; Q86YC3; -.
DR PRIDE; Q86YC3; -.
DR ProteomicsDB; 70396; -.
DR Antibodypedia; 33944; 100 antibodies from 18 providers.
DR DNASU; 375387; -.
DR Ensembl; ENST00000328557.5; ENSP00000328625.4; ENSG00000174004.6.
DR GeneID; 375387; -.
DR KEGG; hsa:375387; -.
DR MANE-Select; ENST00000328557.5; ENSP00000328625.4; NM_198565.3; NP_940967.1.
DR UCSC; uc003fwv.4; human.
DR CTD; 375387; -.
DR DisGeNET; 375387; -.
DR GeneCards; NRROS; -.
DR HGNC; HGNC:24613; NRROS.
DR HPA; ENSG00000174004; Tissue enhanced (bone).
DR MalaCards; NRROS; -.
DR MIM; 615322; gene.
DR MIM; 618875; phenotype.
DR neXtProt; NX_Q86YC3; -.
DR OpenTargets; ENSG00000174004; -.
DR PharmGKB; PA142671521; -.
DR VEuPathDB; HostDB:ENSG00000174004; -.
DR eggNOG; KOG0619; Eukaryota.
DR GeneTree; ENSGT00940000157975; -.
DR HOGENOM; CLU_024194_0_0_1; -.
DR InParanoid; Q86YC3; -.
DR OMA; CLTDFHM; -.
DR OrthoDB; 826997at2759; -.
DR PhylomeDB; Q86YC3; -.
DR TreeFam; TF317167; -.
DR PathwayCommons; Q86YC3; -.
DR SignaLink; Q86YC3; -.
DR BioGRID-ORCS; 375387; 14 hits in 1063 CRISPR screens.
DR ChiTaRS; NRROS; human.
DR GenomeRNAi; 375387; -.
DR Pharos; Q86YC3; Tbio.
DR PRO; PR:Q86YC3; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; Q86YC3; protein.
DR Bgee; ENSG00000174004; Expressed in monocyte and 103 other tissues.
DR Genevisible; Q86YC3; HS.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; IEA:GOC.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0050431; F:transforming growth factor beta binding; IPI:UniProtKB.
DR GO; GO:0006955; P:immune response; ISS:UniProtKB.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0014005; P:microglia development; ISS:UniProtKB.
DR GO; GO:0035583; P:sequestering of TGFbeta in extracellular matrix; ISS:UniProtKB.
DR GO; GO:0006801; P:superoxide metabolic process; ISS:UniProtKB.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0036364; P:transforming growth factor beta1 activation; ISS:UniProtKB.
DR Gene3D; 3.80.10.10; -; 4.
DR InterPro; IPR001611; Leu-rich_rpt.
DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp.
DR InterPro; IPR032675; LRR_dom_sf.
DR Pfam; PF13516; LRR_6; 1.
DR Pfam; PF13855; LRR_8; 3.
DR SMART; SM00369; LRR_TYP; 12.
DR PROSITE; PS51450; LRR; 18.
PE 1: Evidence at protein level;
KW Cell membrane; Disease variant; Disulfide bond; Endoplasmic reticulum;
KW Epilepsy; Glycoprotein; Growth factor binding; Leucine-rich repeat;
KW Membrane; Neurodegeneration; Reference proteome; Repeat; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1..18
FT /evidence="ECO:0000255"
FT CHAIN 19..692
FT /note="Transforming growth factor beta activator LRRC33"
FT /id="PRO_0000042660"
FT TOPO_DOM 19..650
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 651..671
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 672..692
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 29..56
FT /note="LRRNT"
FT /evidence="ECO:0000255"
FT REPEAT 58..79
FT /note="LRR 1"
FT /evidence="ECO:0000255"
FT REPEAT 82..103
FT /note="LRR 2"
FT /evidence="ECO:0000255"
FT REPEAT 106..127
FT /note="LRR 3"
FT /evidence="ECO:0000255"
FT REPEAT 133..155
FT /note="LRR 4"
FT /evidence="ECO:0000255"
FT REPEAT 158..179
FT /note="LRR 5"
FT /evidence="ECO:0000255"
FT REPEAT 182..203
FT /note="LRR 6"
FT /evidence="ECO:0000255"
FT REPEAT 206..227
FT /note="LRR 7"
FT /evidence="ECO:0000255"
FT REPEAT 228..239
FT /note="LRR 8"
FT /evidence="ECO:0000255"
FT REPEAT 251..272
FT /note="LRR 9"
FT /evidence="ECO:0000255"
FT REPEAT 273..294
FT /note="LRR 10"
FT /evidence="ECO:0000255"
FT REPEAT 329..350
FT /note="LRR 11"
FT /evidence="ECO:0000255"
FT REPEAT 353..374
FT /note="LRR 12"
FT /evidence="ECO:0000255"
FT REPEAT 377..398
FT /note="LRR 13"
FT /evidence="ECO:0000255"
FT REPEAT 403..424
FT /note="LRR 14"
FT /evidence="ECO:0000255"
FT REPEAT 427..447
FT /note="LRR 15"
FT /evidence="ECO:0000255"
FT REPEAT 463..484
FT /note="LRR 16"
FT /evidence="ECO:0000255"
FT REPEAT 486..507
FT /note="LRR 17"
FT /evidence="ECO:0000255"
FT REPEAT 512..534
FT /note="LRR 18"
FT /evidence="ECO:0000255"
FT REPEAT 537..558
FT /note="LRR 19"
FT /evidence="ECO:0000255"
FT REPEAT 559..580
FT /note="LRR 20"
FT /evidence="ECO:0000255"
FT REPEAT 585..594
FT /note="LRR 21"
FT /evidence="ECO:0000255"
FT DOMAIN 595..643
FT /note="LRRCT"
FT /evidence="ECO:0000255"
FT CARBOHYD 21
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 74
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 155
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 232
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 292
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 309
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 312
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 408
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 427
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 500
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 622
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 219
FT /note="Interchain (with C-? in TGFB1); in linked form"
FT /evidence="ECO:0000250|UniProtKB:Q8BMT4"
FT DISULFID 363
FT /note="Interchain (with C-? in TGFB1); in linked form"
FT /evidence="ECO:0000250|UniProtKB:Q8BMT4"
FT VARIANT 10
FT /note="L -> P (in SENEBAC; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32197075"
FT /id="VAR_083995"
FT VARIANT 593..692
FT /note="Missing (in SENEBAC; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:32100099"
FT /id="VAR_083996"
SQ SEQUENCE 692 AA; 76366 MW; 1574A06F405DDAA0 CRC64;
MELLPLWLCL GFHFLTVGWR NRSGTATAAS QGVCKLVGGA ADCRGQSLAS VPSSLPPHAR
MLTLDANPLK TLWNHSLQPY PLLESLSLHS CHLERISRGA FQEQGHLRSL VLGDNCLSEN
YEETAAALHA LPGLRRLDLS GNALTEDMAA LMLQNLSSLR SVSLAGNTIM RLDDSVFEGL
ERLRELDLQR NYIFEIEGGA FDGLAELRHL NLAFNNLPCI VDFGLTRLRV LNVSYNVLEW
FLATGGEAAF ELETLDLSHN QLLFFPLLPQ YSKLRTLLLR DNNMGFYRDL YNTSSPREMV
AQFLLVDGNV TNITTVSLWE EFSSSDLADL RFLDMSQNQF QYLPDGFLRK MPSLSHLNLH
QNCLMTLHIR EHEPPGALTE LDLSHNQLSE LHLAPGLASC LGSLRLFNLS SNQLLGVPPG
LFANARNITT LDMSHNQISL CPLPAASDRV GPPSCVDFRN MASLRSLSLE GCGLGALPDC
PFQGTSLTYL DLSSNWGVLN GSLAPLQDVA PMLQVLSLRN MGLHSSFMAL DFSGFGNLRD
LDLSGNCLTT FPRFGGSLAL ETLDLRRNSL TALPQKAVSE QLSRGLRTIY LSQNPYDCCG
VDGWGALQHG QTVADWAMVT CNLSSKIIRV TELPGGVPRD CKWERLDLGL LYLVLILPSC
LTLLVACTVI VLTFKKPLLQ VIKSRCHWSS VY
