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Protein

Mesencephalic astrocyte-derived neurotrophic factor

Gene

MANF

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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). Retained in the ER/sarcoplasmic reticulum (SR) through association with the endoplasmic reticulum chaperone protein HSPA5 under normal conditions (PubMed:22637475). 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).By similarity4 Publications

Caution

Was originally (PubMed:8649854, PubMed:8971156 and 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.Curated
It is uncertain whether Met-1 or Met-4 is the initiator.Curated

GO - Molecular functioni

  • growth factor activity Source: UniProtKB-KW
  • lipid binding Source: UniProtKB
  • RNA binding Source: UniProtKB

GO - Biological processi

  • neuron projection development Source: GO_Central
  • platelet degranulation Source: Reactome
  • regulation of response to endoplasmic reticulum stress Source: UniProtKB
  • response to unfolded protein Source: UniProtKB-KW

Keywordsi

Molecular functionGrowth factor
Biological processStress response, Unfolded protein response
LigandLipid-binding, Sialic acid

Enzyme and pathway databases

ReactomeiR-HSA-114608 Platelet degranulation

Names & Taxonomyi

Protein namesi
Recommended name:
Mesencephalic astrocyte-derived neurotrophic factor
Alternative name(s):
Arginine-rich protein
Protein ARMET
Gene namesi
Name:MANF
Synonyms:ARMET, ARP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Unplaced

Organism-specific databases

HGNCiHGNC:15461 MANF
MIMi601916 gene
neXtProtiNX_P55145

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Endoplasmic reticulum, Sarcoplasmic reticulum, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi112K → L: Reduced sulfatide binding and uptake by target cells. Reduces cytoprotective effect of the wild-type protein. Attenuates stress granule formation in response to endoplasmic reticulum stress. 1 Publication1
Mutagenesisi179 – 182Missing : Two-fold increase in secretion. 1 Publication4
Mutagenesisi179R → K: 14-fold decrease in secretion. 1 Publication1

Organism-specific databases

DisGeNETi7873
PharmGKBiPA24993

Polymorphism and mutation databases

BioMutaiMANF
DMDMi332278201

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 242 PublicationsAdd BLAST24
ChainiPRO_000000230525 – 182Mesencephalic astrocyte-derived neurotrophic factorAdd BLAST158

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi30 ↔ 1171 Publication
Disulfide bondi33 ↔ 1061 Publication
Disulfide bondi64 ↔ 751 Publication
Modified residuei76PhosphotyrosineBy similarity1
Disulfide bondi151 ↔ 1541 Publication

Post-translational modificationi

May contain sialic acid residues.

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP55145
MaxQBiP55145
PaxDbiP55145
PeptideAtlasiP55145
PRIDEiP55145
ProteomicsDBi56793

2D gel databases

OGPiP55145

PTM databases

iPTMnetiP55145
PhosphoSitePlusiP55145

Expressioni

Inductioni

By endoplasmic reticulum stress (PubMed:18561914, PubMed:22637475, PubMed:29497057). By hypoxia (PubMed:29497057).3 Publications

Gene expression databases

CleanExiHS_ARMET
GenevisibleiP55145 HS

Organism-specific databases

HPAiHPA011175

Interactioni

Subunit structurei

Interacts with HSPA5; the interaction is direct.1 Publication

GO - Molecular functioni

Protein-protein interaction databases

BioGridi113621, 12 interactors
IntActiP55145, 4 interactors
MINTiP55145
STRINGi9606.ENSP00000432799

Structurei

Secondary structure

1182
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliP55145
SMRiP55145
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP55145

Family & Domainsi

Domaini

The N-terminal region may be responsible for neurotrophic activity while the C-terminal region may play a role in the ER stress response.1 Publication
The N-terminal region may be required for lipid sulfatide binding.1 Publication

Sequence similaritiesi

Belongs to the ARMET family.Curated

Keywords - Domaini

Signal

Phylogenomic databases

eggNOGiKOG4154 Eukaryota
ENOG4111QMZ LUCA
HOGENOMiHOG000264245
InParanoidiP55145
KOiK22556
PhylomeDBiP55145
TreeFamiTF314252

Family and domain databases

Gene3Di1.10.720.30, 1 hit
InterProiView protein in InterPro
IPR019345 Armet_prot
IPR036361 SAP_dom_sf
PANTHERiPTHR12990 PTHR12990, 1 hit
PfamiView protein in Pfam
PF10208 Armet, 1 hit
SUPFAMiSSF68906 SSF68906, 1 hit

Sequence (1+)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All

P55145-1 [UniParc]FASTAAdd to basket
« Hide
        10         20         30         40         50
MRRMWATQGL AVALALSVLP GSRALRPGDC EVCISYLGRF YQDLKDRDVT
60 70 80 90 100
FSPATIENEL IKFCREARGK ENRLCYYIGA TDDAATKIIN EVSKPLAHHI
110 120 130 140 150
PVEKICEKLK KKDSQICELK YDKQIDLSTV DLKKLRVKEL KKILDDWGET
160 170 180
CKGCAEKSDY IRKINELMPK YAPKAASART DL
Length:182
Mass (Da):20,700
Last modified:May 3, 2011 - v3
Checksum:iEE25A5D1A58D1AD7
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
A8K878A8K878_HUMAN
Mesencephalic astrocyte-derived neu...
MANF
185Annotation score:
H7C2D6H7C2D6_HUMAN
Mesencephalic astrocyte-derived neu...
MANF
71Annotation score:

Sequence cautioni

The sequence AAB08753 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAI13589 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated
The sequence AAI13591 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti13 – 14AL → RV in AAB08753 (PubMed:8649854).Curated2
Sequence conflicti179R → P in AAB08753 (PubMed:8649854).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M83751 mRNA Translation: AAB08753.1 Different initiation.
BT007110 mRNA Translation: AAP35774.1
AC092037 Genomic DNA No translation available.
BC007282 mRNA Translation: AAH07282.1
BC113588 mRNA Translation: AAI13589.1 Different initiation.
BC113590 mRNA Translation: AAI13591.1 Different initiation.
RefSeqiNP_006001.4, NM_006010.5
UniGeneiHs.436446

Genome annotation databases

EnsembliENST00000627526; ENSP00000487450; ENSG00000145050
GeneIDi7873
KEGGihsa:7873
UCSCiuc003dbc.4 human

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M83751 mRNA Translation: AAB08753.1 Different initiation.
BT007110 mRNA Translation: AAP35774.1
AC092037 Genomic DNA No translation available.
BC007282 mRNA Translation: AAH07282.1
BC113588 mRNA Translation: AAI13589.1 Different initiation.
BC113590 mRNA Translation: AAI13591.1 Different initiation.
RefSeqiNP_006001.4, NM_006010.5
UniGeneiHs.436446

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2KVDNMR-A25-182[»]
2KVENMR-A120-182[»]
2W51X-ray2.80A25-182[»]
ProteinModelPortaliP55145
SMRiP55145
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113621, 12 interactors
IntActiP55145, 4 interactors
MINTiP55145
STRINGi9606.ENSP00000432799

PTM databases

iPTMnetiP55145
PhosphoSitePlusiP55145

Polymorphism and mutation databases

BioMutaiMANF
DMDMi332278201

2D gel databases

OGPiP55145

Proteomic databases

EPDiP55145
MaxQBiP55145
PaxDbiP55145
PeptideAtlasiP55145
PRIDEiP55145
ProteomicsDBi56793

Protocols and materials databases

DNASUi7873
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000627526; ENSP00000487450; ENSG00000145050
GeneIDi7873
KEGGihsa:7873
UCSCiuc003dbc.4 human

Organism-specific databases

CTDi7873
DisGeNETi7873
GeneCardsiMANF
HGNCiHGNC:15461 MANF
HPAiHPA011175
MIMi601916 gene
neXtProtiNX_P55145
PharmGKBiPA24993
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG4154 Eukaryota
ENOG4111QMZ LUCA
HOGENOMiHOG000264245
InParanoidiP55145
KOiK22556
PhylomeDBiP55145
TreeFamiTF314252

Enzyme and pathway databases

ReactomeiR-HSA-114608 Platelet degranulation

Miscellaneous databases

EvolutionaryTraceiP55145
GeneWikiiARMET
GenomeRNAii7873
PROiPR:P55145
SOURCEiSearch...

Gene expression databases

CleanExiHS_ARMET
GenevisibleiP55145 HS

Family and domain databases

Gene3Di1.10.720.30, 1 hit
InterProiView protein in InterPro
IPR019345 Armet_prot
IPR036361 SAP_dom_sf
PANTHERiPTHR12990 PTHR12990, 1 hit
PfamiView protein in Pfam
PF10208 Armet, 1 hit
SUPFAMiSSF68906 SSF68906, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiMANF_HUMAN
AccessioniPrimary (citable) accession number: P55145
Secondary accession number(s): Q14CX4, Q86U67, Q96IS4
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: May 3, 2011
Last modified: November 7, 2018
This is version 154 of the entry and version 3 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  3. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  4. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
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Main funding by: National Institutes of Health

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