ID MANF_HUMAN Reviewed; 182 AA. AC P55145; Q14CX4; Q86U67; Q96IS4; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 03-MAY-2011, sequence version 3. DT 04-NOV-2026, entry version 196. DE RecName: Full=Mesencephalic astrocyte-derived neurotrophic factor {ECO:0000305}; DE AltName: Full=Arginine-rich protein; DE AltName: Full=Protein ARMET; DE Flags: Precursor; GN Name=MANF {ECO:0000312|HGNC:HGNC:15461}; Synonyms=ARMET, ARP; 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], AND DISCUSSION OF A PUTATIVE CANCER VARIANT. RX PubMed=8649854; RA Shridhar V., Rivard S., Shridhar R., Mullins C., Bostick L., Sakr W., RA Grignon D., Miller O.J., Smith D.I.; RT "A gene from human chromosomal band 3p21.1 encodes a highly conserved RT arginine-rich protein and is mutated in renal cell carcinomas."; RL Oncogene 12:1931-1939(1996). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Colon, and Eye; 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 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 PROTEIN SEQUENCE OF 25-39. RC TISSUE=Platelet; RX PubMed=12665801; DOI=10.1038/nbt810; RA Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., RA Vandekerckhove J.; RT "Exploring proteomes and analyzing protein processing by mass spectrometric RT identification of sorted N-terminal peptides."; RL Nat. Biotechnol. 21:566-569(2003). RN [6] RP PROTEIN SEQUENCE OF 25-29, FUNCTION, SUBCELLULAR LOCATION, AND RP GLYCOSYLATION. RX PubMed=12794311; DOI=10.1385/jmn:20:2:173; RA Petrova P., Raibekas A., Pevsner J., Vigo N., Anafi M., Moore M.K., RA Peaire A.E., Shridhar V., Smith D.I., Kelly J., Durocher Y., RA Commissiong J.W.; RT "MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with RT selectivity for dopaminergic neurons."; RL J. Mol. Neurosci. 20:173-188(2003). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=15144186; DOI=10.1021/ac035352d; RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., RA Peters E.C.; RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from RT human T cells using immobilized metal affinity chromatography and tandem RT mass spectrometry."; RL Anal. Chem. 76:2763-2772(2004). RN [8] RP FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION. RX PubMed=18561914; DOI=10.1016/j.yexcr.2008.05.001; RA Apostolou A., Shen Y., Liang Y., Luo J., Fang S.; RT "Armet, a UPR-upregulated protein, inhibits cell proliferation and ER RT stress-induced cell death."; RL Exp. Cell Res. 314:2454-2467(2008). RN [9] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [10] RP FUNCTION, INTERACTION WITH HSPA5, SUBCELLULAR LOCATION, INDUCTION, AND RP MUTAGENESIS OF 179-ARG--LYS-182 AND ARG-179. RX PubMed=22637475; DOI=10.1074/jbc.m112.356345; RA Glembotski C.C., Thuerauf D.J., Huang C., Vekich J.A., Gottlieb R.A., RA Doroudgar S.; RT "Mesencephalic astrocyte-derived neurotrophic factor protects the heart RT from ischemic damage and is selectively secreted upon sarco/endoplasmic RT reticulum calcium depletion."; RL J. Biol. Chem. 287:25893-25904(2012). RN [11] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, INDUCTION, DOMAIN, AND MUTAGENESIS OF RP LYS-112. RX PubMed=29497057; DOI=10.1038/s41467-018-03355-0; RA Bai M., Vozdek R., Hnizda A., Jiang C., Wang B., Kuchar L., Li T., RA Zhang Y., Wood C., Feng L., Dang Y., Ma D.K.; RT "Conserved roles of C. elegans and human MANFs in sulfatide binding and RT cytoprotection."; RL Nat. Commun. 9:897-897(2018). RN [14] RP FUNCTION, INTERACTION WITH ERN1, AND INDUCTION. RX PubMed=36739529; DOI=10.1016/j.celrep.2023.112066; RA Kovaleva V., Yu L.Y., Ivanova L., Shpironok O., Nam J., Eesmaa A., RA Kumpula E.P., Sakson S., Toots U., Ustav M., Huiskonen J.T., RA Voutilainen M.H., Lindholm P., Karelson M., Saarma M.; RT "MANF regulates neuronal survival and UPR through its ER-located receptor RT IRE1alpha."; RL Cell Rep. 42:112066-112066(2023). RN [15] RP X-RAY CRYSTALLOGRAPHY, DOMAIN, AND DISULFIDE BONDS. RX PubMed=19258449; DOI=10.1093/protein/gzn080; RA Parkash V., Lindholm P., Peranen J., Kalkkinen N., Oksanen E., Saarma M., RA Leppanen V.-M., Goldman A.; RT "The structure of the conserved neurotrophic factors MANF and CDNF explains RT why they are bifunctional."; RL Protein Eng. Des. Sel. 22:233-241(2009). RN [16] RP DISCUSSION OF A PUTATIVE CANCER VARIANT. RX PubMed=8971156; RA Shridhar R., Shridhar V., Rivard S., Siegfried J.M., Pietraszkiewicz H., RA Ensley J., Pauley R., Grignon D., Sakr W., Miller O.J., Smith D.I.; RT "Mutations in the arginine-rich protein gene, in lung, breast, and prostate RT cancers, and in squamous cell carcinoma of the head and neck."; RL Cancer Res. 56:5576-5578(1996). RN [17] RP DISCUSSION OF PUTATIVE CANCER VARIANTS. RX PubMed=9174057; DOI=10.1038/sj.onc.1201054; RA Shridhar V., Rivard S., Wang X., Shridhar R., Paisley C., Mullins C., RA Beirnat L., Dugan M., Sarkar F., Miller O.J., Vaitkevicius V.K., RA Smith D.I.; RT "Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer."; RL Oncogene 14:2213-2216(1997). RN [18] RP INVOLVEMENT IN DDDS. RX PubMed=26077850; DOI=10.1007/s00439-015-1575-0; RA Yavarna T., Al-Dewik N., Al-Mureikhi M., Ali R., Al-Mesaifri F., RA Mahmoud L., Shahbeck N., Lakhani S., AlMulla M., Nawaz Z., Vitazka P., RA Alkuraya F.S., Ben-Omran T.; RT "High diagnostic yield of clinical exome sequencing in Middle Eastern RT patients with Mendelian disorders."; RL Hum. Genet. 134:967-980(2015). RN [19] RP INVOLVEMENT IN DDDS. RX PubMed=33500254; DOI=10.2337/db20-1174; RA Montaser H., Patel K.A., Balboa D., Ibrahim H., Lithovius V., RA Naeaetaenen A., Chandra V., Demir K., Acar S., Ben-Omran T., Colclough K., RA Locke J.M., Wakeling M., Lindahl M., Hattersley A.T., Saarimaeki-Vire J., RA Otonkoski T.; RT "Loss of MANF causes childhood-onset syndromic diabetes due to increased RT endoplasmic reticulum stress."; RL Diabetes 70:1006-1018(2021). CC -!- FUNCTION: Selectively promotes the survival of dopaminergic neurons of CC the ventral mid-brain (PubMed:12794311). Modulates GABAergic CC transmission to the dopaminergic neurons of the substantia nigra (By CC similarity). Enhances spontaneous, as well as evoked, GABAergic CC inhibitory postsynaptic currents in dopaminergic neurons (By CC similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) CC stress-induced cell death (PubMed:18561914, PubMed:22637475, CC PubMed:29497057, PubMed:36739529). Retained in the ER/sarcoplasmic CC reticulum (SR) through association with the endoplasmic reticulum CC chaperone protein HSPA5 under normal conditions (PubMed:22637475). CC Stabilizes HSPA5/BiP in its substrate-bound ADP state, which CC facilitates HSPA5/BiP incorporation into chaperone-client complexes CC during endoplasmic reticulum stress, its interaction with HSPA5/BiP CC inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange CC (By similarity). As a result acts as a repressor of the unfolded CC protein response (UPR) pathway (By similarity). Up-regulated and CC secreted by the ER/SR in response to ER stress and hypoxia CC (PubMed:22637475). Following secretion by the ER/SR, directly binds to CC 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell CC membrane of target cells (PubMed:29497057). Sulfatide binding promotes CC its cellular uptake by endocytosis, and is required for its role in CC alleviating ER stress and cell toxicity under hypoxic and ER stress CC conditions (PubMed:29497057). Essential for embryonic lung development CC (By similarity). Required for the correct postnatal temporal and CC structural development of splenic white pulp (By similarity). Required CC for the repair-associated myeloid response in skeletal muscle, acts as CC a regulator of phenotypic transition towards prorepair macrophages in CC response to muscle injury and as a result limits excessive pro- CC inflammatory signaling (By similarity). Represses RELA expression and CC therefore NF-kB signaling in the myocardium, as a result limits CC macrophage infiltration of injured tissue and M1 macrophage CC differentiation in response to myocardial injury (By similarity). CC Required for endochondral ossification in long bones and the skull CC during postnatal development (By similarity). CC {ECO:0000250|UniProtKB:P0C5H9, ECO:0000250|UniProtKB:Q9CXI5, CC ECO:0000269|PubMed:12794311, ECO:0000269|PubMed:18561914, CC ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:29497057, CC ECO:0000269|PubMed:36739529}. CC -!- SUBUNIT: Interacts directly (via SAP domain) with HSPA5/BiP; the CC interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide CC exchange (PubMed:22637475). Component of a complex containing at least CC CRELD2, MANF, MATN3 and PDIA4 (By similarity). Interacts (via C- CC terminus) with ERN1 (via luminal domain); the interaction is decreased CC in the presence of increasing concentrations of Ca(2+) CC (PubMed:36739529). {ECO:0000250|UniProtKB:Q9CXI5, CC ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:36739529}. CC -!- INTERACTION: CC P55145; Q5TBC7: BCL2L15; NbExp=2; IntAct=EBI-1044104, EBI-10247136; CC P55145; Q16799-3: RTN1; NbExp=4; IntAct=EBI-1044104, EBI-10180131; CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:12794311, CC ECO:0000269|PubMed:18561914, ECO:0000269|PubMed:22637475, CC ECO:0000269|PubMed:29497057}. Endoplasmic reticulum lumen CC {ECO:0000305|PubMed:29497057}. Sarcoplasmic reticulum lumen CC {ECO:0000269|PubMed:22637475}. Note=Retained in the endoplasmic CC reticulum (ER), and sarcoplasmic reticulum (SR) under normal conditions CC (PubMed:22637475). Up-regulated and secreted by the ER/SR in response CC to ER stress and hypoxia (PubMed:22637475, PubMed:29497057). CC {ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:29497057}. CC -!- INDUCTION: By endoplasmic reticulum stress (PubMed:18561914, CC PubMed:22637475, PubMed:29497057). By hypoxia (PubMed:29497057). CC Induced by the ER stressor tunicamycin (PubMed:36739529). CC {ECO:0000269|PubMed:18561914, ECO:0000269|PubMed:22637475, CC ECO:0000269|PubMed:29497057, ECO:0000269|PubMed:36739529}. CC -!- DOMAIN: The N-terminal region may be responsible for neurotrophic CC activity while the C-terminal region may play a role in the ER stress CC response. {ECO:0000269|PubMed:19258449}. CC -!- DOMAIN: The N-terminal region may be required for lipid sulfatide CC binding. {ECO:0000269|PubMed:29497057}. CC -!- PTM: May contain sialic acid residues. CC -!- DISEASE: Diabetes, deafness, developmental delay, and short stature CC syndrome (DDDS) [MIM:620651]: An autosomal recessive, multisystem CC disorder characterized by childhood-onset non-autoimmune diabetes CC mellitus, short stature, bilateral sensorineural deafness, CC developmental delay, mildly impaired intellectual development, and CC microcephaly. {ECO:0000269|PubMed:26077850, CC ECO:0000269|PubMed:33500254}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the ARMET family. {ECO:0000305}. CC -!- CAUTION: Was originally (PubMed:8649854, PubMed:8971156, CC PubMed:9174057) thought to be much longer and included an arginine-rich CC region thought to be the target of cancer-causing mutations. All these CC mutations are in what is now thought to be the 5'-UTR of the mRNA. CC {ECO:0000305}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-4 is the initiator. CC {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAB08753.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAI13589.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAI13591.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M83751; AAB08753.1; ALT_INIT; mRNA. DR EMBL; BT007110; AAP35774.1; -; mRNA. DR EMBL; AC092037; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC007282; AAH07282.1; -; mRNA. DR EMBL; BC113588; AAI13589.1; ALT_INIT; mRNA. DR EMBL; BC113590; AAI13591.1; ALT_INIT; mRNA. DR CCDS; CCDS46836.4; -. DR RefSeq; NP_006001.5; NM_006010.6. DR PDB; 2KVD; NMR; -; A=25-182. DR PDB; 2KVE; NMR; -; A=120-182. DR PDB; 2W51; X-ray; 2.80 A; A=25-182. DR AlphaFoldDB; P55145; -. DR MDposit; P55145; -. DR SMR; P55145; -. DR BioGRID; 113621; 132. DR FunCoup; P55145; 1691. DR IntAct; P55145; 50. DR NDEx; MUSIC2-C5172-MANF; Osteosarcoma (U2OS) cell map - Endoplasmic reticulum (98 proteins). DR STRING; 9606.ENSP00000499582; -. DR GlyGen; P55145; 1 site, 1 O-linked glycan (1 site). DR iPTMnet; P55145; -. DR MetOSite; P55145; -. DR PhosphoSitePlus; P55145; -. DR SwissPalm; P55145; -. DR BioMuta; MANF; -. DR DMDM; 332278201; -. DR OGP; P55145; -. DR CPTAC; CPTAC-403; -. DR CPTAC; CPTAC-404; -. DR jPOST; P55145; -. DR MassIVE; P55145; -. DR PaxDb; 9606-ENSP00000499582; -. DR PeptideAtlas; P55145; -. DR ProteomicsDB; 56793; -. DR Pumba; P55145; -. DR Antibodypedia; 2505; 401 antibodies from 38 providers. DR DNASU; 7873; -. DR Ensembl; ENST00000528157.7; ENSP00000432799.3; ENSG00000145050.19. DR GeneID; 7873; -. DR KEGG; hsa:7873; -. DR MANE-Select; ENST00000528157.7; ENSP00000432799.3; NM_006010.6; NP_006001.5. DR UCSC; uc003dbc.4; human. DR AGR; HGNC:15461; -. DR ClinPGx; PA24993; -. DR CTD; 7873; -. DR DisGeNET; 7873; -. DR GeneCards; MANF; -. DR HGNC; HGNC:15461; MANF. DR HPA; ENSG00000145050; Low tissue specificity. DR MalaCards; MANF; -. DR MIM; 601916; gene. DR MIM; 620651; phenotype. DR OpenTargets; ENSG00000145050; -. DR VEuPathDB; HostDB:ENSG00000145050; -. DR eggNOG; KOG4154; Eukaryota. DR GeneTree; ENSGT00390000007160; -. DR HOGENOM; CLU_099080_1_0_1; -. DR InParanoid; P55145; -. DR OMA; AALWKLC; -. DR OrthoDB; 5597848at2759; -. DR PAN-GO; P55145; 4 GO annotations based on evolutionary models. DR PhylomeDB; P55145; -. DR PathwayCommons; P55145; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR SignaLink; P55145; -. DR Agora; ENSG00000145050; Agora Nominated Target for Alzheimer's Disease. DR BioGRID-ORCS; 7873; 206 hits in 1155 CRISPR screens. DR CD-CODE; 91857CE7; Nucleolus. DR ChiTaRS; MANF; human. DR EvolutionaryTrace; P55145; -. DR GeneWiki; ARMET; -. DR GenomeRNAi; 7873; -. DR Pharos; P55145; Tbio. DR PRO; PR:P55145; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; P55145; protein. DR Bgee; ENSG00000145050; Expressed in islet of Langerhans and 199 other cell types or tissues. DR ExpressionAtlas; P55145; baseline and differential. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HPA. DR GO; GO:0005788; C:endoplasmic reticulum lumen; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; EXP:UniProtKB. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0033018; C:sarcoplasmic reticulum lumen; EXP:UniProtKB. DR GO; GO:0008083; F:growth factor activity; EXP:GO_Central. DR GO; GO:0003723; F:RNA binding; HDA:UniProtKB. DR GO; GO:0120146; F:sulfatide binding; IPI:UniProtKB. DR GO; GO:0071542; P:dopaminergic neuron differentiation; IBA:GO_Central. DR GO; GO:0031175; P:neuron projection development; IBA:GO_Central. DR GO; GO:1905897; P:regulation of response to endoplasmic reticulum stress; IMP:UniProtKB. DR DisProt; DP03191; -. DR FunFam; 1.10.225.10:FF:000003; Mesencephalic astrocyte-derived neurotrophic factor; 1. DR FunFam; 1.10.720.30:FF:000003; Mesencephalic astrocyte-derived neurotrophic factor; 1. DR Gene3D; 1.10.720.30; SAP domain; 1. DR Gene3D; 1.10.225.10; Saposin-like; 1. DR InterPro; IPR045333; ARMET-like. DR InterPro; IPR019345; ARMET_C. DR InterPro; IPR045332; ARMET_N. DR InterPro; IPR036361; SAP_dom_sf. DR PANTHER; PTHR12990; ARMET-LIKE PROTEIN; 1. DR PANTHER; PTHR12990:SF10; MESENCEPHALIC ASTROCYTE-DERIVED NEUROTROPHIC FACTOR; 1. DR Pfam; PF10208; ARMET_C; 1. DR Pfam; PF20145; ARMET_N; 1. DR SUPFAM; SSF68906; SAP domain; 1. PE 1: Evidence at protein level; KW 3D-structure; Deafness; Diabetes mellitus; Direct protein sequencing; KW Disulfide bond; Dwarfism; Endoplasmic reticulum; Glycoprotein; KW Growth factor; Lipid-binding; Phosphoprotein; Proteomics identification; KW Reference proteome; Sarcoplasmic reticulum; Secreted; Sialic acid; Signal; KW Stress response; Unfolded protein response. FT SIGNAL 1..24 FT /evidence="ECO:0000269|PubMed:12665801, FT ECO:0000269|PubMed:12794311" FT CHAIN 25..182 FT /note="Mesencephalic astrocyte-derived neurotrophic factor" FT /id="PRO_0000002305" FT REGION 96..158 FT /note="Interacts with ERN1, EIF2AK3 and ATF6" FT /evidence="ECO:0000269|PubMed:36739529" FT REGION 129..172 FT /note="Interacts with HSPA5" FT /evidence="ECO:0000250|UniProtKB:Q9CXI5" FT MOD_RES 76 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:Q9CXI5" FT DISULFID 30..117 FT /evidence="ECO:0000269|PubMed:19258449" FT DISULFID 33..106 FT /evidence="ECO:0000269|PubMed:19258449" FT DISULFID 64..75 FT /evidence="ECO:0000269|PubMed:19258449" FT DISULFID 151..154 FT /evidence="ECO:0000269|PubMed:19258449" FT MUTAGEN 112 FT /note="K->L: Reduced sulfatide binding and uptake by target FT cells. Reduces cytoprotective effect of the wild-type FT protein. Attenuates stress granule formation in response to FT endoplasmic reticulum stress." FT /evidence="ECO:0000269|PubMed:29497057" FT MUTAGEN 179..182 FT /note="Missing: Two-fold increase in secretion." FT /evidence="ECO:0000269|PubMed:22637475" FT MUTAGEN 179 FT /note="R->K: 14-fold decrease in secretion." FT /evidence="ECO:0000269|PubMed:22637475" FT CONFLICT 13..14 FT /note="AL -> RV (in Ref. 1; AAB08753)" FT /evidence="ECO:0000305" FT CONFLICT 179 FT /note="R -> P (in Ref. 1; AAB08753)" FT /evidence="ECO:0000305" FT HELIX 31..46 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 53..64 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 69..77 FT /evidence="ECO:0007829|PDB:2W51" FT STRAND 81..83 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 87..89 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 90..97 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 102..112 FT /evidence="ECO:0007829|PDB:2W51" FT TURN 115..118 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 127..129 FT /evidence="ECO:0007829|PDB:2KVD" FT TURN 132..134 FT /evidence="ECO:0007829|PDB:2KVD" FT HELIX 136..143 FT /evidence="ECO:0007829|PDB:2W51" FT HELIX 155..158 FT /evidence="ECO:0007829|PDB:2W51" FT TURN 166..173 FT /evidence="ECO:0007829|PDB:2KVD" SQ SEQUENCE 182 AA; 20700 MW; EE25A5D1A58D1AD7 CRC64; MRRMWATQGL AVALALSVLP GSRALRPGDC EVCISYLGRF YQDLKDRDVT FSPATIENEL IKFCREARGK ENRLCYYIGA TDDAATKIIN EVSKPLAHHI PVEKICEKLK KKDSQICELK YDKQIDLSTV DLKKLRVKEL KKILDDWGET CKGCAEKSDY IRKINELMPK YAPKAASART DL //