Q8N5K1 (CISD2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
CDGSH iron-sulfur domain-containing protein 2

Alternative name(s):
Endoplasmic reticulum intermembrane small protein
MitoNEET-related 1 protein
Short name=Miner1
Nutrient-deprivation autophagy factor-1
Short name=NAF-1

Gene names

Name:	CISD2
Synonyms:	CDGSH2, ERIS, ZCD2

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	135 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Regulator of autophagy that contributes to antagonize BECN1-mediated cellular autophagy at the endoplasmic reticulum. Participates in the interaction of BCL2 with BECN1 and is required for BCL2-mediated depression of endoplasmic reticulum Ca2+ stores during autophagy. Contributes to BIK-initiated autophagy, while it is not involved in BIK-dependent activation of caspases. Involved in life span control, probably via its function as regulator of autophagy. Ref.1 Ref.8
Cofactor	Binds 1 2Fe-2S cluster. Ref.7
Subunit structure	Homodimer. Interacts with BCL2; the interaction is direct and disrupted by BIK interaction with BCL2. Interacts with BCL2L1. Interacts with ITPR1. Ref.8
Subcellular location	Endoplasmic reticulum membrane; Single-pass membrane protein. Mitochondrion outer membrane; Single-pass membrane protein. Note: According to Ref.8, it mainly localizes to the endoplasmic reticulum. However, experiments in mouse showed that it mainly localizes to the mitochondrion outer membrane. Ref.1 Ref.7 Ref.8
Tissue specificity	Testis, small intestine, kidney, lung, brain, heart, pancreas and platelets. Ref.1
Involvement in disease	Wolfram syndrome 2 (WFS2) [MIM:604928]: A rare disorder characterized by juvenile-onset insulin-dependent diabetes mellitus with optic atrophy. Other manifestations include diabetes insipidus, sensorineural deafness, dementia, psychiatric illnesses. WFS2 patients additionally show a strong bleeding tendency and gastrointestinal ulceration. Diabetes insipidus may be absent. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1
Sequence similarities	Belongs to the CISD protein family. CISD2 subfamily.
Caution	Although initially thought (Ref.1) to be a zinc-finger protein, it was later shown (Ref.7) that it binds 1 2Fe-2S cluster instead.
Biophysicochemical properties	Redox potential: E is 0 +/- 10 mV for 2Fe-2S at pH 7.5. Ref.10
Sequence caution	The sequence CAD97935.1 differs from that shown. Reason: Erroneous initiation.

Ontologies

Keywords
Biological process	Autophagy
Cellular component	Endoplasmic reticulum Membrane Mitochondrion Mitochondrion outer membrane
Disease	Deafness Diabetes mellitus
Domain	Transmembrane Transmembrane helix
Ligand	2Fe-2S Iron Iron-sulfur Metal-binding
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	mitochondrion degradation Inferred from electronic annotation. Source: Compara multicellular organismal aging Inferred from sequence or structural similarity. Source: UniProtKB regulation of autophagy Inferred from mutant phenotype Ref.8. Source: UniProtKB
Cellular_component	endoplasmic reticulum membrane Inferred from direct assay Ref.8. Source: UniProtKB integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrial outer membrane Inferred from sequence or structural similarity. Source: UniProtKB protein complex Inferred from direct assay. Source: LIFEdb
Molecular_function	2 iron, 2 sulfur cluster binding Inferred from direct assay Ref.10. Source: UniProtKB metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein homodimerization activity Inferred from direct assay Ref.10. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 135

135

CDGSH iron-sulfur domain-containing protein 2

PRO_0000316005

Regions

Topological domain

1 – 37

37

Lumenal Potential

Transmembrane

38 – 60

23

Helical; Potential

Topological domain

61 – 135

75

Cytoplasmic Potential

Sites

Metal binding

99

1

Iron-sulfur (2Fe-2S)

Metal binding

101

1

Iron-sulfur (2Fe-2S)

Metal binding

110

1

Iron-sulfur (2Fe-2S)

Metal binding

114

1

Iron-sulfur (2Fe-2S); via pros nitrogen

Experimental info

Mutagenesis

92

1

C → S: Has the same optical signature of the native protein and improves yields of purified protein and a decreased tendency to aggregate. Ref.10

Mutagenesis

99

1

C → S: Impairs interaction with BCL2; when associated with S-101; S-110 and Q-114. Ref.8

Mutagenesis

101

1

C → S: Impairs interaction with BCL2; when associated with S-99; S-110 and Q-114. Ref.8

Mutagenesis

110

1

C → S: Impairs interaction with BCL2; when associated with S-99; S-101 and Q-114. Ref.8

Mutagenesis

114

1

H → Q: Impairs interaction with BCL2; when associated with S-99; S-101 and S-110. Ref.8

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

135

Helix Strand Turn

Details...

Beta strand

73 – 75

3

Beta strand

79 – 87

9

Helix

88 – 90

3

Beta strand

93 – 98

6

Beta strand

100 – 102

3

Turn

105 – 108

4

Helix

113 – 121

9

Beta strand

125 – 131

7

Sequences

	Sequence		Length	Mass (Da)
	Q8N5K1 [UniParc]. Last modified October 1, 2002. Version 1. Checksum: 44AD1817D6C536D6	FASTA	135	15,278
	10 20 30 40 50 60 MVLESVARIV KVQLPAYLKR LPVPESITGF ARLTVSEWLR LLPFLGVLAL LGYLAVRPFL 70 80 90 100 110 120 PKKKQQKDSL INLKIQKENP KVVNEINIED LCLTKAAYCR CWRSKTFPAC DGSHNKHNEL 130 TGDNVGPLIL KKKEV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2." Amr S., Heisey C., Zhang M., Xia X.J., Shows K.H., Ajlouni K., Pandya A., Satin L.S., El-Shanti H., Shiang R. Am. J. Hum. Genet. 81:673-683(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, INVOLVEMENT IN WFS2.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Synovium.
[3]	"The full-ORF clone resource of the German cDNA consortium." Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I. BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Retina.
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	"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: Cervix.
[6]	Bienvenut W.V. Submitted (JUN-2005) to UniProtKB Cited for: PROTEIN SEQUENCE OF 21-32; 82-95 AND 117-131, MASS SPECTROMETRY. Tissue: B-cell lymphoma.
[7]	"MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity." Wiley S.E., Murphy A.N., Ross S.A., van der Geer P., Dixon J.E. Proc. Natl. Acad. Sci. U.S.A. 104:5318-5323(2007) [PubMed] [Europe PMC] [Abstract] Cited for: COFACTOR, SUBCELLULAR LOCATION.
[8]	"Antagonism of Beclin 1-dependent autophagy by BCL-2 at the endoplasmic reticulum requires NAF-1." Chang N.C., Nguyen M., Germain M., Shore G.C. EMBO J. 29:606-618(2010) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH BCL2; BCL2L1 AND ITPR1, MUTAGENESIS OF CYS-99; CYS-101; CYS-110 AND HIS-114.
[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]	"Crystal structure of Miner1: The redox-active 2Fe-2S protein causative in Wolfram Syndrome 2." Conlan A.R., Axelrod H.L., Cohen A.E., Abresch E.C., Zuris J., Yee D., Nechushtai R., Jennings P.A., Paddock M.L. J. Mol. Biol. 392:143-153(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 57-135 OF MUTANT CYS-92 IN COMPLEX WITH 2FE-2S, BIOPHYSICOCHEMICAL PROPERTIES, MUTAGENESIS OF CYS-92.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AK292134 mRNA. Translation: BAF84823.1.
BX537971 mRNA. Translation: CAD97935.1. Different initiation.
CH471057 Genomic DNA. Translation: EAX06148.1.
BC032300 mRNA. Translation: AAH32300.1.

IPI

IPI00166865.

RefSeq

NP_001008389.1. NM_001008388.4.

UniGene

Hs.444955.
Hs.556638.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3FNV	X-ray	2.10	A/B	57-135	[»]

ProteinModelPortal

Q8N5K1.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000273986.

PTM databases

PhosphoSite

Q8N5K1.

Polymorphism databases

DMDM

74729013.

Proteomic databases

PaxDb

Q8N5K1.

PeptideAtlas

Q8N5K1.

PRIDE

Q8N5K1.

Protocols and materials databases

DNASU

493856.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000273986; ENSP00000273986; ENSG00000145354.

GeneID

493856.

KEGG

hsa:493856.

UCSC

uc003hwt.4. human.

Organism-specific databases

CTD

493856.

GeneCards

GC04P103790.

HGNC

HGNC:24212. CISD2.

HPA

HPA015914.

MIM

604928. phenotype.
611507. gene.

neXtProt

NX_Q8N5K1.

Orphanet

3463. Wolfram syndrome.

PharmGKB

PA162382300.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG236423.

HOGENOM

HOG000242301.

HOVERGEN

HBG052444.

InParanoid

Q8N5K1.

OMA

YLTIRPF.

OrthoDB

EOG4H9XN0.

PhylomeDB

Q8N5K1.

Gene expression databases

ArrayExpress

Q8N5K1.

Bgee

Q8N5K1.

CleanEx

HS_CISD2.

Genevestigator

Q8N5K1.

Family and domain databases

InterPro

IPR018967. FeS-contain_CDGSH-typ.
IPR006622. FeS-contain_CDGSH-typ_subfam.
IPR019610. FeS-contain_mitoNEET_N.
[Graphical view]

Pfam

PF10660. MitoNEET_N. 1 hit.
PF09360. zf-CDGSH. 1 hit.
[Graphical view]

SMART

SM00704. ZnF_CDGSH. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

CISD2. human.

EvolutionaryTrace

Q8N5K1.

GenomeRNAi

493856.

NextBio

111774.

SOURCE

Search...

Entry information

Entry name

CISD2_HUMAN

Accession

Primary (citable) accession number: Q8N5K1
Secondary accession number(s): Q7Z3D5

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 15, 2008
Last sequence update:	October 1, 2002
Last modified:	May 1, 2013
This is version 81 of the entry and version 1 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.