LGMN_MOUSE
ID LGMN_MOUSE Reviewed; 435 AA.
AC O89017;
DT 24-JUN-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1998, sequence version 1.
DT 03-AUG-2022, entry version 159.
DE RecName: Full=Legumain;
DE EC=3.4.22.34;
DE AltName: Full=Asparaginyl endopeptidase;
DE AltName: Full=Protease, cysteine 1;
DE Flags: Precursor;
GN Name=Lgmn; Synonyms=Prsc1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR
RP LOCATION, BIOPHYSICOCHEMICAL PROPERTIES, AND TISSUE SPECIFICITY.
RX PubMed=9742219; DOI=10.1042/bj3350111;
RA Chen J.-M., Dando P.M., Stevens R.A.E., Fortunato M., Barrett A.J.;
RT "Cloning and expression of mouse legumain, a lysosomal endopeptidase.";
RL Biochem. J. 335:111-117(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=9821970; DOI=10.1016/s0014-5793(98)01281-2;
RA Halfon S., Patel S., Vega F., Zurawski S., Zurawski G.;
RT "Autocatalytic activation of human legumain at aspartic acid residues.";
RL FEBS Lett. 438:114-118(1998).
RN [3]
RP ACTIVE SITE, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-47; CYS-52; HIS-150
RP AND CYS-191.
RX PubMed=9891971; DOI=10.1016/s0014-5793(98)01574-9;
RA Chen J.-M., Rawlings N.D., Stevens R.A., Barrett A.J.;
RT "Identification of the active site of legumain links it to caspases,
RT clostripain and gingipains in a new clan of cysteine endopeptidases.";
RL FEBS Lett. 441:361-365(1998).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17350006; DOI=10.1016/j.febslet.2007.02.064;
RA Morita Y., Araki H., Sugimoto T., Takeuchi K., Yamane T., Maeda T.,
RA Yamamoto Y., Nishi K., Asano M., Shirahama-Noda K., Nishimura M., Uzu T.,
RA Hara-Nishimura I., Koya D., Kashiwagi A., Ohkubo I.;
RT "Legumain/asparaginyl endopeptidase controls extracellular matrix
RT remodeling through the degradation of fibronectin in mouse renal proximal
RT tubular cells.";
RL FEBS Lett. 581:1417-1424(2007).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [6]
RP DISRUPTION PHENOTYPE, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=21292981; DOI=10.1096/fj.10-172312;
RA Miller G., Matthews S.P., Reinheckel T., Fleming S., Watts C.;
RT "Asparagine endopeptidase is required for normal kidney physiology and
RT homeostasis.";
RL FASEB J. 25:1606-1617(2011).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.01 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP SUBUNIT, AUTOCATALYTIC PROCESSING, DISULFIDE BOND, GLYCOSYLATION,
RP PROPEPTIDE, MUTAGENESIS OF ASN-44; ARG-46; HIS-150; GLU-189; CYS-191;
RP ASP-233 AND ASP-311, AND ACTIVITY REGULATION.
RX PubMed=24407422; DOI=10.1038/cr.2014.4;
RA Zhao L., Hua T., Crowley C., Ru H., Ni X., Shaw N., Jiao L., Ding W.,
RA Qu L., Hung L.W., Huang W., Liu L., Ye K., Ouyang S., Cheng G., Liu Z.J.;
RT "Structural analysis of asparaginyl endopeptidase reveals the activation
RT mechanism and a reversible intermediate maturation stage.";
RL Cell Res. 24:344-358(2014).
CC -!- FUNCTION: Has a strict specificity for hydrolysis of asparaginyl bonds.
CC Can also cleave aspartyl bonds slowly, especially under acidic
CC conditions. May be involved in the processing of proteins for MHC class
CC II antigen presentation in the lysosomal/endosomal system. Required for
CC normal lysosomal protein degradation in renal proximal tubules.
CC Required for normal degradation of internalized EGFR. Plays a role in
CC the regulation of cell proliferation via its role in EGFR degradation.
CC {ECO:0000269|PubMed:17350006, ECO:0000269|PubMed:21292981,
CC ECO:0000269|PubMed:24407422, ECO:0000269|PubMed:9742219}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=Hydrolysis of proteins and small molecule substrates at
CC -Asn-|-Xaa- bonds.; EC=3.4.22.34;
CC Evidence={ECO:0000269|PubMed:24407422, ECO:0000269|PubMed:9742219,
CC ECO:0000269|PubMed:9891971};
CC -!- ACTIVITY REGULATION: Inhibited by cystatin-C.
CC {ECO:0000269|PubMed:24407422}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC pH dependence:
CC Optimum pH is 6. {ECO:0000269|PubMed:9742219};
CC -!- SUBUNIT: May interact with integrins (By similarity). Monomer after
CC autocatalytic processing. Homodimer before autocatalytic removal of the
CC propeptide. {ECO:0000250, ECO:0000269|PubMed:24407422}.
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:21292981,
CC ECO:0000269|PubMed:9742219}.
CC -!- TISSUE SPECIFICITY: Detected in kidney proximal tubules (at protein
CC level). Ubiquitous. Particularly abundant in kidney and placenta.
CC {ECO:0000269|PubMed:21292981, ECO:0000269|PubMed:9742219}.
CC -!- DOMAIN: In the zymogen form, the uncleaved propeptide blocks access to
CC the active site. {ECO:0000250}.
CC -!- PTM: Glycosylated. {ECO:0000305|PubMed:24407422}.
CC -!- PTM: Activated by autocatalytic processing at pH 4.
CC -!- DISRUPTION PHENOTYPE: Young mice initially display no obvious
CC phenotype, but fail to gain weight normally. Mutant mice display pale
CC kidneys with abnormal proliferation of proximal tubule cells, proximal
CC tubule hyperplasia and develop kidney interstitium fibrosis. After 6
CC months, mutant mice display a decreased glomerular filtration rate,
CC increased plasma creatinine levels and proteinuria. Glomerular
CC lysosomes do not show a generalized defect in protein catabolism.
CC Instead they show defects in the degradation of a set of target
CC proteins, including EGFR. {ECO:0000269|PubMed:17350006,
CC ECO:0000269|PubMed:21292981}.
CC -!- SIMILARITY: Belongs to the peptidase C13 family. {ECO:0000305}.
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DR EMBL; AJ000990; CAA04439.1; -; mRNA.
DR EMBL; AF044266; AAF21659.1; -; mRNA.
DR CCDS; CCDS26119.1; -.
DR RefSeq; NP_035305.1; NM_011175.3.
DR PDB; 4NOJ; X-ray; 2.80 A; A=27-289.
DR PDB; 4NOK; X-ray; 2.50 A; A=1-435.
DR PDB; 4NOL; X-ray; 2.70 A; A/B=1-435.
DR PDB; 4NOM; X-ray; 2.01 A; A=1-435.
DR PDBsum; 4NOJ; -.
DR PDBsum; 4NOK; -.
DR PDBsum; 4NOL; -.
DR PDBsum; 4NOM; -.
DR AlphaFoldDB; O89017; -.
DR SMR; O89017; -.
DR BioGRID; 202402; 9.
DR STRING; 10090.ENSMUSP00000021607; -.
DR BindingDB; O89017; -.
DR ChEMBL; CHEMBL1949492; -.
DR MEROPS; C13.004; -.
DR GlyConnect; 2463; 1 N-Linked glycan (1 site).
DR GlyGen; O89017; 4 sites, 1 N-linked glycan (1 site).
DR iPTMnet; O89017; -.
DR MetOSite; O89017; -.
DR PhosphoSitePlus; O89017; -.
DR SwissPalm; O89017; -.
DR EPD; O89017; -.
DR jPOST; O89017; -.
DR MaxQB; O89017; -.
DR PaxDb; O89017; -.
DR PeptideAtlas; O89017; -.
DR PRIDE; O89017; -.
DR ProteomicsDB; 286191; -.
DR Antibodypedia; 17; 331 antibodies from 28 providers.
DR DNASU; 19141; -.
DR Ensembl; ENSMUST00000021607; ENSMUSP00000021607; ENSMUSG00000021190.
DR Ensembl; ENSMUST00000110020; ENSMUSP00000105647; ENSMUSG00000021190.
DR GeneID; 19141; -.
DR KEGG; mmu:19141; -.
DR UCSC; uc007oue.1; mouse.
DR CTD; 5641; -.
DR MGI; MGI:1330838; Lgmn.
DR VEuPathDB; HostDB:ENSMUSG00000021190; -.
DR eggNOG; KOG1348; Eukaryota.
DR GeneTree; ENSGT00940000154782; -.
DR HOGENOM; CLU_024160_2_0_1; -.
DR InParanoid; O89017; -.
DR OMA; HCFNWHL; -.
DR OrthoDB; 826971at2759; -.
DR PhylomeDB; O89017; -.
DR TreeFam; TF313403; -.
DR BRENDA; 3.4.22.34; 3474.
DR Reactome; R-MMU-1679131; Trafficking and processing of endosomal TLR.
DR Reactome; R-MMU-2132295; MHC class II antigen presentation.
DR BioGRID-ORCS; 19141; 1 hit in 74 CRISPR screens.
DR ChiTaRS; Lgmn; mouse.
DR PRO; PR:O89017; -.
DR Proteomes; UP000000589; Chromosome 12.
DR RNAct; O89017; protein.
DR Bgee; ENSMUSG00000021190; Expressed in stroma of bone marrow and 268 other tissues.
DR ExpressionAtlas; O89017; baseline and differential.
DR Genevisible; O89017; MM.
DR GO; GO:0045177; C:apical part of cell; IDA:MGI.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005576; C:extracellular region; ISO:MGI.
DR GO; GO:0005770; C:late endosome; IDA:MGI.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0004197; F:cysteine-type endopeptidase activity; IDA:UniProtKB.
DR GO; GO:0008233; F:peptidase activity; IMP:MGI.
DR GO; GO:0097202; P:activation of cysteine-type endopeptidase activity; ISO:MGI.
DR GO; GO:0008306; P:associative learning; IGI:ARUK-UCL.
DR GO; GO:1904646; P:cellular response to amyloid-beta; ISO:MGI.
DR GO; GO:0071277; P:cellular response to calcium ion; ISO:MGI.
DR GO; GO:0035729; P:cellular response to hepatocyte growth factor stimulus; ISO:MGI.
DR GO; GO:0097061; P:dendritic spine organization; IGI:ARUK-UCL.
DR GO; GO:0007613; P:memory; IGI:ARUK-UCL.
DR GO; GO:1901185; P:negative regulation of ERBB signaling pathway; IMP:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; ISO:MGI.
DR GO; GO:0040015; P:negative regulation of multicellular organism growth; IMP:MGI.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISO:MGI.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI.
DR GO; GO:2001028; P:positive regulation of endothelial cell chemotaxis; ISO:MGI.
DR GO; GO:1900273; P:positive regulation of long-term synaptic potentiation; IGI:ARUK-UCL.
DR GO; GO:0045931; P:positive regulation of mitotic cell cycle; ISO:MGI.
DR GO; GO:0090026; P:positive regulation of monocyte chemotaxis; ISO:MGI.
DR GO; GO:0006508; P:proteolysis; IDA:UniProtKB.
DR GO; GO:0051603; P:proteolysis involved in protein catabolic process; IMP:UniProtKB.
DR GO; GO:0032801; P:receptor catabolic process; IMP:UniProtKB.
DR GO; GO:0003014; P:renal system process; IMP:UniProtKB.
DR GO; GO:0010447; P:response to acidic pH; IMP:ARUK-UCL.
DR GO; GO:0097264; P:self proteolysis; ISO:MGI.
DR GO; GO:0006624; P:vacuolar protein processing; IBA:GO_Central.
DR InterPro; IPR043577; AE.
DR InterPro; IPR001096; Peptidase_C13.
DR PANTHER; PTHR12000; PTHR12000; 1.
DR Pfam; PF01650; Peptidase_C13; 1.
DR PIRSF; PIRSF500139; AE; 1.
DR PIRSF; PIRSF019663; Legumain; 1.
DR PRINTS; PR00776; HEMOGLOBNASE.
PE 1: Evidence at protein level;
KW 3D-structure; Disulfide bond; Glycoprotein; Hydrolase; Lysosome; Protease;
KW Reference proteome; Signal; Thiol protease; Zymogen.
FT SIGNAL 1..17
FT /evidence="ECO:0000250"
FT CHAIN 18..325
FT /note="Legumain"
FT /id="PRO_0000026504"
FT PROPEP 326..435
FT /id="PRO_0000026505"
FT ACT_SITE 150
FT /evidence="ECO:0000269|PubMed:9891971"
FT ACT_SITE 191
FT /note="Nucleophile"
FT /evidence="ECO:0000269|PubMed:9891971"
FT SITE 325..326
FT /note="Cleavage; by autolysis"
FT CARBOHYD 93
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 169
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 265
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 274
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 380..414
FT /evidence="ECO:0000269|PubMed:24407422"
FT DISULFID 392..431
FT /evidence="ECO:0000269|PubMed:24407422"
FT MUTAGEN 44
FT /note="N->A: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:24407422"
FT MUTAGEN 46
FT /note="R->A: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:24407422"
FT MUTAGEN 47
FT /note="H->A: 54% Loss of activity."
FT /evidence="ECO:0000269|PubMed:9891971"
FT MUTAGEN 52
FT /note="C->S: No loss of activity."
FT /evidence="ECO:0000269|PubMed:9891971"
FT MUTAGEN 150
FT /note="H->A: Complete loss of activity. Abolishes
FT autocatalytic processing."
FT /evidence="ECO:0000269|PubMed:24407422,
FT ECO:0000269|PubMed:9891971"
FT MUTAGEN 189
FT /note="E->A: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:24407422"
FT MUTAGEN 191
FT /note="C->A,S: Abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:24407422,
FT ECO:0000269|PubMed:9891971"
FT MUTAGEN 233
FT /note="D->A: Abolishes enzyme activity. Abolishes
FT autocatalytic processing."
FT /evidence="ECO:0000269|PubMed:24407422"
FT MUTAGEN 311
FT /note="D->A: Nearly abolishes enzyme activity."
FT /evidence="ECO:0000269|PubMed:24407422"
FT STRAND 31..37
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 42..44
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 45..60
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 68..71
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 76..79
FT /evidence="ECO:0007829|PDB:4NOJ"
FT STRAND 89..91
FT /evidence="ECO:0007829|PDB:4NOL"
FT HELIX 107..109
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 112..120
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 124..126
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 142..149
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 155..157
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 159..164
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 165..177
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 182..190
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 193..196
FT /evidence="ECO:0007829|PDB:4NOM"
FT TURN 197..199
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 202..212
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 219..224
FT /evidence="ECO:0007829|PDB:4NOM"
FT TURN 225..228
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 229..233
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 234..245
FT /evidence="ECO:0007829|PDB:4NOM"
FT TURN 248..250
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 253..263
FT /evidence="ECO:0007829|PDB:4NOM"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 275..279
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 283..286
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 309..311
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 312..323
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 327..359
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 363..370
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 378..391
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 401..406
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 407..415
FT /evidence="ECO:0007829|PDB:4NOM"
FT HELIX 420..431
FT /evidence="ECO:0007829|PDB:4NOM"
SQ SEQUENCE 435 AA; 49373 MW; F956B9E10098013D CRC64;
MTWRVAVLLS LVLGAGAVPV GVDDPEDGGK HWVVIVAGSN GWYNYRHQAD ACHAYQIIHR
NGIPDEQIIV MMYDDIANSE ENPTPGVVIN RPNGTDVYKG VLKDYTGEDV TPENFLAVLR
GDAEAVKGKG SGKVLKSGPR DHVFIYFTDH GATGILVFPN DDLHVKDLNK TIRYMYEHKM
YQKMVFYIEA CESGSMMNHL PDDINVYATT AANPKESSYA CYYDEERGTY LGDWYSVNWM
EDSDVEDLTK ETLHKQYHLV KSHTNTSHVM QYGNKSISTM KVMQFQGMKH RASSPISLPP
VTHLDLTPSP DVPLTILKRK LLRTNDVKES QNLIGQIQQF LDARHVIEKS VHKIVSLLAG
FGETAERHLS ERTMLTAHDC YQEAVTHFRT HCFNWHSVTY EHALRYLYVL ANLCEAPYPI
DRIEMAMDKV CLSHY
