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 27-MAR-2024, entry version 185. 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 X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 25-182, DOMAIN, AND DISULFIDE RP 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 [15] 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 [16] 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). 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). Retained in the ER/sarcoplasmic reticulum (SR) CC through association with the endoplasmic reticulum chaperone protein CC HSPA5 under normal conditions (PubMed:22637475). 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). {ECO:0000250|UniProtKB:P0C5H9, CC ECO:0000269|PubMed:12794311, ECO:0000269|PubMed:18561914, CC ECO:0000269|PubMed:22637475, ECO:0000269|PubMed:29497057}. CC -!- SUBUNIT: Interacts with HSPA5; the interaction is direct CC (PubMed:22637475). Component of a complex containing at least CRELD2, CC MANF, MATN3 and PDIA4 (By similarity). {ECO:0000250|UniProtKB:Q9CXI5, CC ECO:0000269|PubMed:22637475}. CC -!- INTERACTION: 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 {ECO:0000269|PubMed:18561914, ECO:0000269|PubMed:22637475, CC ECO:0000269|PubMed:29497057}. 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 -!- 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_006001.4; NM_006010.5. 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 PDBsum; 2KVD; -. DR PDBsum; 2KVE; -. DR PDBsum; 2W51; -. DR AlphaFoldDB; P55145; -. DR SMR; P55145; -. DR BioGRID; 113621; 113. DR IntAct; P55145; 29. DR MINT; P55145; -. DR STRING; 9606.ENSP00000499582; -. 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 EPD; P55145; -. DR jPOST; P55145; -. DR MassIVE; P55145; -. DR MaxQB; P55145; -. DR PaxDb; 9606-ENSP00000432799; -. DR PeptideAtlas; P55145; -. DR ProteomicsDB; 56793; -. DR Pumba; P55145; -. DR Antibodypedia; 2505; 395 antibodies from 35 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 CTD; 7873; -. DR DisGeNET; 7873; -. DR GeneCards; MANF; -. DR HGNC; HGNC:15461; MANF. DR HPA; ENSG00000145050; Low tissue specificity. DR MIM; 601916; gene. DR neXtProt; NX_P55145; -. DR OpenTargets; ENSG00000145050; -. DR PharmGKB; PA24993; -. DR VEuPathDB; HostDB:ENSG00000145050; -. DR eggNOG; KOG4154; Eukaryota. DR GeneTree; ENSGT00390000007160; -. DR HOGENOM; CLU_099080_1_0_1; -. DR InParanoid; P55145; -. DR OMA; EVCKGCA; -. DR OrthoDB; 49731at2759; -. DR PhylomeDB; P55145; -. DR TreeFam; TF314252; -. DR PathwayCommons; P55145; -. DR Reactome; R-HSA-114608; Platelet degranulation. DR SignaLink; P55145; -. DR BioGRID-ORCS; 7873; 206 hits in 1155 CRISPR screens. 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; IBA:GO_Central. DR GO; GO:0005788; C:endoplasmic reticulum lumen; IDA:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005634; C:nucleus; HDA:UniProtKB. DR GO; GO:0033018; C:sarcoplasmic reticulum lumen; IEA:UniProtKB-SubCell. DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW. 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 GO; GO:0006986; P:response to unfolded protein; IEA:UniProtKB-KW. DR GO; GO:0002014; P:vasoconstriction of artery involved in ischemic response to lowering of systemic arterial blood pressure; IEA:Ensembl. 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. DR Genevisible; P55145; HS. PE 1: Evidence at protein level; KW 3D-structure; Direct protein sequencing; Disulfide bond; KW Endoplasmic reticulum; Glycoprotein; Growth factor; Lipid-binding; KW Phosphoprotein; Reference proteome; Sarcoplasmic reticulum; Secreted; KW Sialic acid; Signal; 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 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 //