P55145 (MANF_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mesencephalic astrocyte-derived neurotrophic factor

Alternative name(s):
Arginine-rich protein
Protein ARMET

Gene names

Name:	MANF
Synonyms:	ARMET, ARP

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	182 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Selectively promotes the survival of dopaminergic neurons of the ventral mid-brain. Modulates GABAergic transmission to the dopaminergic neurons of the substantia nigra. 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. Ref.6 Ref.8
Subcellular location	Secreted Ref.6 Ref.8.
Induction	By endoplasmic reticulum stress. Ref.8
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. Ref.10
Post-translational modification	May contain sialic acid residues.
Sequence similarities	Belongs to the ARMET family.
Caution	Was originally (Ref.1, Ref.11 and Ref.12) 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. It is uncertain whether Met-1 or Met-4 is the initiator.
Sequence caution	The sequence AAB08753.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence AAI13589.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened. The sequence AAI13591.1 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
Biological process	Unfolded protein response
Cellular component	Secreted
Domain	Signal
Ligand	Sialic acid
Molecular function	Growth factor
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	response to unfolded protein Inferred from electronic annotation. Source: UniProtKB-KW vasoconstriction of artery involved in ischemic response to lowering of systemic arterial blood pressure Inferred from electronic annotation. Source: Compara
Cellular_component	extracellular space Inferred from electronic annotation. Source: Compara perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 24

24

Ref.5 Ref.6

Chain

25 – 182

158

Mesencephalic astrocyte-derived neurotrophic factor

PRO_0000002305

Amino acid modifications

Modified residue

7

1

Phosphothreonine Ref.7

Modified residue

17

1

Phosphoserine Ref.7

Modified residue

76

1

Phosphotyrosine By similarity

Disulfide bond

30 ↔ 117

Ref.10

Disulfide bond

33 ↔ 106

Ref.10

Disulfide bond

64 ↔ 75

Ref.10

Disulfide bond

151 ↔ 154

Ref.10

Experimental info

Sequence conflict

13 – 14

2

AL → RV in AAB08753. Ref.1

Sequence conflict

179

1

R → P in AAB08753. Ref.1

Secondary structure

1

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182

Helix Strand Turn

Details...

Helix

31 – 46

16

Helix

53 – 64

12

Helix

69 – 77

9

Beta strand

81 – 83

3

Helix

87 – 89

3

Helix

90 – 97

8

Helix

102 – 112

11

Turn

115 – 118

4

Helix

127 – 129

3

Turn

132 – 134

3

Helix

136 – 143

8

Helix

155 – 158

4

Turn

166 – 173

8

Sequences

	Sequence		Length	Mass (Da)
	P55145 [UniParc]. Last modified May 3, 2011. Version 3. Checksum: EE25A5D1A58D1AD7	FASTA	182	20,700
	10 20 30 40 50 60 MRRMWATQGL AVALALSVLP GSRALRPGDC EVCISYLGRF YQDLKDRDVT FSPATIENEL 70 80 90 100 110 120 IKFCREARGK ENRLCYYIGA TDDAATKIIN EVSKPLAHHI PVEKICEKLK KKDSQICELK 130 140 150 160 170 180 YDKQIDLSTV DLKKLRVKEL KKILDDWGET CKGCAEKSDY IRKINELMPK YAPKAASART DL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A gene from human chromosomal band 3p21.1 encodes a highly conserved arginine-rich protein and is mutated in renal cell carcinomas." Shridhar V., Rivard S., Shridhar R., Mullins C., Bostick L., Sakr W., Grignon D., Miller O.J., Smith D.I. Oncogene 12:1931-1939(1996) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], DISCUSSION OF A PUTATIVE CANCER VARIANT.
[2]	"Cloning of human full-length CDSs in BD Creator(TM) system donor vector." Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A. Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Colon and Eye.
[4]	"The DNA sequence, annotation and analysis of human chromosome 3." Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J. , Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A. Nature 440:1194-1198(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides." Gevaert K., Goethals M., Martens L., Van Damme J., Staes A., Thomas G.R., Vandekerckhove J. Nat. Biotechnol. 21:566-569(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-39. Tissue: Platelet.
[6]	"MANF: a new mesencephalic, astrocyte-derived neurotrophic factor with selectivity for dopaminergic neurons." Petrova P., Raibekas A., Pevsner J., Vigo N., Anafi M., Moore M.K., Peaire A.E., Shridhar V., Smith D.I., Kelly J., Durocher Y., Commissiong J.W. J. Mol. Neurosci. 20:173-188(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 25-29, FUNCTION, SUBCELLULAR LOCATION, GLYCOSYLATION.
[7]	"Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry." Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M., Peters E.C. Anal. Chem. 76:2763-2772(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-7 AND SER-17, MASS SPECTROMETRY. Tissue: Leukemic T-cell.
[8]	"Armet, a UPR-upregulated protein, inhibits cell proliferation and ER stress-induced cell death." Apostolou A., Shen Y., Liang Y., Luo J., Fang S. Exp. Cell Res. 314:2454-2467(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INDUCTION.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"The structure of the conserved neurotrophic factors MANF and CDNF explains why they are bifunctional." Parkash V., Lindholm P., Peranen J., Kalkkinen N., Oksanen E., Saarma M., Leppanen V.-M., Goldman A. Protein Eng. Des. Sel. 22:233-241(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 25-182, DOMAIN, DISULFIDE BONDS.
[11]	"Mutations in the arginine-rich protein gene, in lung, breast, and prostate cancers, and in squamous cell carcinoma of the head and neck." Shridhar R., Shridhar V., Rivard S., Siegfried J.M., Pietraszkiewicz H., Ensley J., Pauley R., Grignon D., Sakr W., Miller O.J., Smith D.I. Cancer Res. 56:5576-5578(1996) [PubMed] [Europe PMC] [Abstract] Cited for: DISCUSSION OF A PUTATIVE CANCER VARIANT.
[12]	"Mutations in the arginine-rich protein gene (ARP) in pancreatic cancer." Shridhar V., Rivard S., Wang X., Shridhar R., Paisley C., Mullins C., Beirnat L., Dugan M., Sarkar F., Miller O.J., Vaitkevicius V.K., Smith D.I. Oncogene 14:2213-2216(1997) [PubMed] [Europe PMC] [Abstract] Cited for: DISCUSSION OF PUTATIVE CANCER VARIANTS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00980165.

RefSeq

NP_006001.3. NM_006010.4.

UniGene

Hs.436446.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2KVD	NMR	-	A	25-182	[»]
2KVE	NMR	-	A	120-182	[»]
2W51	X-ray	2.80	A	25-181	[»]

ProteinModelPortal

P55145.

SMR

P55145. Positions 25-161.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000273628.

PTM databases

PhosphoSite

P55145.

Polymorphism databases

DMDM

23503040.

2D gel databases

OGP

P55145.

Proteomic databases

PaxDb

P55145.

PRIDE

P55145.

Protocols and materials databases

DNASU

7873.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000528157; ENSP00000432799; ENSG00000145050.
ENST00000566546; ENSP00000454660; ENSG00000259880.

GeneID

7873.

KEGG

hsa:7873.

UCSC

uc003dbc.3. human.

Organism-specific databases

CTD

7873.

GeneCards

GC03P051399.

HGNC

HGNC:15461. MANF.

HPA

HPA011175.

MIM

601916. gene.

neXtProt

NX_P55145.

Orphanet

1333. Familial pancreatic carcinoma.

PharmGKB

PA24993.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG301491.

HOGENOM

HOG000264245.

InParanoid

P55145.

OrthoDB

EOG4VT5Z8.

Gene expression databases

ArrayExpress

P55145.

Bgee

P55145.

CleanEx

HS_ARMET.

Genevestigator

P55145.

GermOnline

ENSG00000145050. Homo sapiens.

Family and domain databases

Gene3D

1.10.225.10. 1 hit.

InterPro

IPR019345. Armet_prot.
IPR011001. Saposin-like.
[Graphical view]

Pfam

PF10208. Armet. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P55145.

GenomeRNAi

7873.

NextBio

30328.

SOURCE

Search...

Entry information

Entry name

MANF_HUMAN

Accession

Primary (citable) accession number: P55145
Secondary accession number(s): Q14CX4, Q86U67, Q96IS4

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	May 3, 2011
Last modified:	April 3, 2013
This is version 108 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.