UniProt:P55145 MANF

chain
  • signal peptide:1-24
  • chain:25-182
checksum EE25A5D1A58D1AD7
comment
  • FUNCTION Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain (PubMed:12794311). Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra (By similarity). Enhances spontaneous, as well as evoked, GABAergic inhibitory postsynaptic currents in dopaminergic neurons (By similarity). Inhibits cell proliferation and endoplasmic reticulum (ER) stress-induced cell death (PubMed:18561914, PubMed:22637475, PubMed:29497057, PubMed:36739529). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). Stabilizes HSPA5/BiP in its substrate-bound ADP state, which facilitates HSPA5/BiP incorporation into chaperone-client complexes during endoplasmic reticulum stress, its interaction with HSPA5/BiP inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (By similarity). As a result acts as a repressor of the unfolded protein response (UPR) pathway (By similarity). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475). Following secretion by the ER/SR, directly binds to 3-O-sulfogalactosylceramide, a lipid sulfatide in the outer cell membrane of target cells (PubMed:29497057). Sulfatide binding promotes its cellular uptake by endocytosis, and is required for its role in alleviating ER stress and cell toxicity under hypoxic and ER stress conditions (PubMed:29497057). Essential for embryonic lung development (By similarity). Required for the correct postnatal temporal and structural development of splenic white pulp (By similarity). Required for the repair-associated myeloid response in skeletal muscle, acts as a regulator of phenotypic transition towards prorepair macrophages in response to muscle injury and as a result limits excessive proinflammatory signaling (By similarity). Represses RELA expression and therefore NF-kB signaling in the myocardium, as a result limits macrophage infiltration of injured tissue and M1 macrophage differentiation in response to myocardial injury (By similarity). Required for endochondral ossification in long bones and the skull during postnatal development (By similarity).SUBUNIT Interacts directly (via SAP domain) with HSPA5/BiP; the interaction inhibits ATP binding to HSPA5/BiP and subsequent nucleotide exchange (PubMed:22637475). Component of a complex containing at least CRELD2, MANF, MATN3 and PDIA4 (By similarity). Interacts (via C-terminus) with ERN1 (via luminal domain); the interaction is decreased in the presence of increasing concentrations of Ca(2+) (PubMed:36739529).INTERACTION Retained in the endoplasmic reticulum (ER), and sarcoplasmic reticulum (SR) under normal conditions (PubMed:22637475). Up-regulated and secreted by the ER/SR in response to ER stress and hypoxia (PubMed:22637475, PubMed:29497057).INDUCTION By endoplasmic reticulum stress (PubMed:18561914, PubMed:22637475, PubMed:29497057). By hypoxia (PubMed:29497057). Induced by the ER stressor tunicamycin (PubMed:36739529).DOMAIN The N-terminal region may be responsible for neurotrophic activity while the C-terminal region may play a role in the ER stress response.DOMAIN The N-terminal region may be required for lipid sulfatide binding.PTM May contain sialic acid residues.DISEASE The disease is caused by variants affecting the gene represented in this entry.SIMILARITY Belongs to the ARMET family.CAUTION Was originally (PubMed:8649854, PubMed:8971156, PubMed:9174057) thought to be much longer and included an arginine-rich region thought to be the target of cancer-causing mutations. All these mutations are in what is now thought to be the 5'-UTR of the mRNA.CAUTION It is uncertain whether Met-1 or Met-4 is the initiator.SEQUENCE CAUTION Extended N-terminus.SEQUENCE CAUTION Extended N-terminus.SEQUENCE CAUTION Extended N-terminus.
crossReference
databaseName UniProt
dbId 50293
description
  • recommendedName: fullName evidence="12"Mesencephalic astrocyte-derived neurotrophic factor alternativeName: Arginine-rich protein alternativeName: Protein ARMET
displayName UniProt:P55145 MANF
geneName
  • MANF
  • ARMET
  • ARP
identifier P55145
isSequenceChanged false
keyword
  • 3D-structure
  • Deafness
  • Diabetes mellitus
  • Direct protein sequencing
  • Disulfide bond
  • Dwarfism
  • Endoplasmic reticulum
  • Glycoprotein
  • Growth factor
  • Lipid-binding
  • Phosphoprotein
  • Proteomics identification
  • Reference proteome
  • Sarcoplasmic reticulum
  • Secreted
  • Sialic acid
  • Signal
  • Stress response
  • Unfolded protein response
modified [InstanceEdit:9963647] Weiser, Joel, 2025-08-15
moleculeType Protein
name
  • MANF
otherIdentifier
  • 11715795_at
  • 16941167
  • 202655_PM_at
  • 202655_at
  • 2623140
  • 2623141
  • 2623142
  • 2623143
  • 2623144
  • 2623145
  • 2623146
  • 2623148
  • 2623149
  • 2623151
  • 2623152
  • 2623153
  • 36615_at
  • 7873
  • 8080084
  • A_14_P131439
  • A_23_P132793
  • GE58108
  • GO:0002014
  • GO:0003013
  • GO:0003723
  • GO:0005515
  • GO:0005576
  • GO:0005615
  • GO:0005634
  • GO:0005783
  • GO:0005788
  • GO:0005829
  • GO:0006986
  • GO:0008083
  • GO:0008289
  • GO:0016529
  • GO:0031175
  • GO:0033018
  • GO:0036500
  • GO:0048018
  • GO:0071542
  • GO:0098772
  • GO:0120146
  • GO:1905897
  • HMNXSV003014889
  • ILMN_2183510
  • M83751_at
  • PH_hs_0033391
  • TC03000319.hg
  • g5174392_3p_at
physicalEntity
referenceDatabase [ReferenceDatabase:2] UniProt
referenceGene
referenceTranscript
schemaClass ReferenceGeneProduct
secondaryIdentifier
  • MANF_HUMAN
  • Q14CX4
  • Q86U67
  • Q96IS4
sequenceLength 182
species [Species:48887] Homo sapiens
stId uniprot:P55145
url http://purl.uniprot.org/uniprot/P55145
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